Review article

The role of N(6)-methyladenosine (m6a) modification in cancer: recent advances and future directions

Xiaozhou Xie1, Zhen Fang2, Haoyu Zhang1, Zheng Wang1, Jie Li1, Yuchen Jia1, Liang Shang2[*], Feng Cao1, Fei Li1

1Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China

2Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China

EXCLI J 2025;24:Doc113

 

Abstract

N(6)-methyladenosine (m6A) modification is the most abundant and prevalent internal modification in eukaryotic mRNAs. The role of m6A modification in cancer has become a hot research topic in recent years and has been widely explored. m6A modifications have been shown to regulate cancer occurrence and progression by modulating different target molecules. This paper reviews the recent research progress of m6A modifications in cancer and provides an outlook on future research directions, especially the development of molecularly targeted drugs.

See also the graphical abstract(Fig. 1).

Keywords: N(6)-methyladenosine (m6A), writers, erasers, readers, cancer

Introduction

Post-transcriptional modification of RNA is a key component of epigenetics, and to date, more than 170 identified RNA modifications, including RNA methylation, have been identified (Roundtree et al., 2017[203]). In the 1970s, adenosine was shown to be methylated at the nitrogen atom of N(6), forming N(6)-methyladenosine (m6A) (Desrosiers et al., 1974[46]). The m6A modification mainly occurs on the adenine in the RRACH sequence, with significant enrichment at the 3'UTR and near stop codons, and its modification is dynamically reversible (Meyer et al., 2012[172]). Currently, m6A modifications have been identified as the most abundant and prevalent internal modifications in eukaryotic mRNAs (Jiang et al., 2021[109]). With the development of Next-generation sequencing, breakthroughs have been made in the role of m6A modifications in eukaryotes (Tavakoli et al., 2023[236]; Chen et al., 2015[21]). m6A modifications are closely associated with almost all aspects of RNA-related biological processes, including transcription, precursor mRNA splicing and processing, nuclear export, translation, RNA stability and decay (Lesbirel et al., 2018[120]; Wang et al., 2014[274], 2022[266]). In addition to this, m6A modifications are also involved in other biological processes, such as transcriptional regulation and signal transduction (Zhang et al., 2024[337]; Patil et al., 2016[188]; Lee et al., 2021[118], 2021[119]). m6A dysregulation contributes to the development of a wide range of human diseases. Notably, m6A modifications play an important regulatory role in the occurrence and development of human cancer. It has been found that m6A regulates cancer progression through its involvement in the regulation of autophagy (Yu et al., 2024[324]), cell cycle (Xu et al., 2024[304]; Xia et al., 2024[299]), DNA damage (Cesaro et al., 2024[12]), ferroptosis (Wu et al., 2023[296]), chemotherapeutic resistance (Zhou et al., 2024[364]), and oncogenes/anti-oncogenes expression (Wang et al., 2024[279], 2023[273]). This review summarizes the research progress of m6A modification in cancer and looks into the future trends and possible research directions of m6A modification.

The Writers, Erasers, and Readers of m6A

Enzymes are involved in the exercise of m6A function, including methylation transferase (writer), demethylation enzyme (eraser) and methylation recognition protein (reader) (Yang et al., 2018[318]). Writers include METTL3/4/5/14/16, WTAP, VIRMA, RBM15, RBM15B, ZC3H13 and ZCCHC4. Erasers include FTO, ALKBH5. Readers include IGF2BP1/2/3, YTHDF1/2/3, YTHDC1/2, HNRNPC, HNRNPG, HNRNPA2B1, FMRP, and PRRC2A. These m6A regulators play different roles (Table 1(Tab. 1); References in Table 1: Alarcón et al., 2015[1]; Bokar et al., 1997[8]; Chang et al., 2020[13]; Chen et al., 2020[17], 2022[28]; Goh et al., 2020[62]; Hsu et al., 2017[81], 2019[80]; Huang et al., 2018[91], 2021[94]; Liu et al., 2014[151], 2015[154]; Patil et al., 2016[188]; Pendleton et al., 2017[189]; Ping et al., 2014[191]; Ren et al., 2019[199], 2023[200]; Roundtree et al., 2017[204]; Sepich-Poore et al., 2022[205]; Shi et al., 2017[211]; Wang et al., 2014[274], 2015[276], 2016[259]; Warda et al., 2017[280]; Wei et al., 2018[282]; Wen et al., 2018[286]; Wu et al., 2019[292], 2024[294]; Xiao et al., 2016[300]; Yue et al., 2018[329]; Zhang et al., 2018[339]; Zhao et al., 2020[357]; Zheng et al., 2013[358]; Zhou et al., 2019[362]), and their dysregulation or aberrant expression affects cancer progression and thus the clinical prognosis of cancer patients.

Writers

METTL3, a core component of the m6A methyltransferase complex (MTC), was first characterized in 1997 (Bokar et al., 1997[8]). METTL3 and METTL14 form a heterodimeric complex that co-catalyzes m6A modification, with METTL3 being the catalytic subunit that binds S-adenosylmethionine (SAM), and METTL14 playing a crucial structural role in substrate recognition (Wang et al., 2016[259]; Liu et al., 2014[151]). METTL3 plays a pro-carcinogenic role in most malignant tumors (Cheng et al., 2024[33]; Bhattarai et al., 2024[6]; Vaid et al., 2024[239]), but also acts as a cancer suppressor in certain tumors (Chen et al., 2024[26]; Zhang et al., 2024[335]). METTL14 also exerts oncogenic and anticancer effects in different tumors. METTL14 promotes cell proliferation of myeloid proliferative neoplasms by regulating SETBP1 (Jiang et al., 2024[106]). METTL14 downregulates CircUGGT2 to inhibit the progression of gastric cancer (Chen et al., 2024[29]).

WTAP does not have methylation activity, but its interaction with the METTL3-METTL14 complex is required for their localization to nuclear speckles enriched in pre-mRNA processing factors (Liu et al., 2014[151]; Ping et al., 2014[191]). WTAP affects tumor progression by regulating cell cycle (Jin et al., 2024[114]), mitophagy (Wang et al., 2024[254]), production of reactive oxygen species (Ji et al., 2024[99]), oxidative phosphorylation (Jia et al., 2023[104]), ferroptosis (Tan et al., 2024[231]; Wang et al., 2023[256]), and chemotherapy drug resistance (Wei et al., 2021[283]).

METTL4 is a methyltransferase of U2 snRNA that regulates RNA splicing (Chen et al., 2020[17]; Goh et al., 2020[62]). Currently, it has been found that METTL4 affects tumor development by regulating ferroptosis (Liu et al., 2023[158]; Shen et al., 2021[209]).

METTL5 catalyzes the m6A modification of nucleotide A-1832 in human 18S rRNA (van Tran et al., 2019[240]). It contains one active site, one substrate binding site, and one catalytic site (van Tran et al., 2019[240]; Turkalj and Vissers, 2022[238]). The research on METTL5 in cancer has emerged in recent years, and current research is mostly focused on the field of hepatocellular carcinoma (Xia et al., 2023[298]; Wang and Peng, 2023[257]; Luo et al., 2024[164]; Wang et al., 2024[262]; Xu et al., 2023[306]).

The methylation substrates of METTL16 must meet specific sequential and structural requirements (Doxtader et al., 2018[51]; Mendel et al., 2018[171]), so the abundance of substrates for METTL16 is very low, and so far only two substrates, the MAT2A transcript encoding SAM synthase and the U6 snRNA, have been confirmed (Pendleton et al., 2017[189]; Warda et al., 2017[280]).

VIRMA (KIAA1429) is located in the nuclear speckles (Zhu et al., 2021[375]), and as the largest known component of the MTC (202 kDa), it participates in the formation of the MTC and acts as a scaffold, and recruits the m6A complex to specific RNA sites (Yue et al., 2018[329]). VIRMA was found to promote hepatocellular carcinoma progression by regulating the m6A modification of GATA3 (Lan et al., 2019[116]) and lung adenocarcinoma by regulating BTG2 (Zhang et al., 2022[338]) and JNK/MAPK pathways (Lin et al., 2023[146]).

RBM15 collaborates with its analog RBM15B to recruit MTC to specific sites of long noncoding RNA X inactivation-specific transcript (XIST) and promote XIST-mediated gene silencing (Patil et al., 2016[188]). In recent years, the research results of RBM15 in cancer have been remarkable, and it has been found that RBM15 acts as an oncogene in breast cancer (Park et al., 2024[187]), laryngeal cancer (Wang et al., 2021[275]), pancreatic cancer (Dong et al., 2023[49]), bladder cancer (Huang et al., 2024[95]), esophageal squamous carcinoma (Wang, 2024[245]), renal clear cell carcinoma (Zeng et al., 2022[330]), cervical cancer (Song and Wu, 2023[216]), and ovarian cancer (Yuan et al., 2023[326]).

ZC3H13 regulates m6A methylation by inducing nuclear localization of ZC3H13-WTAP-Vrilizer-Hakai complex (Zhao et al., 2020[357]; Wen et al., 2018[286]). ZC3H13 plays dual roles in different tumors. ZC3H13 enhances cervical cancer stemness and chemotherapy resistance by promoting m6A modification of CENPK (Lin et al., 2022[145]). ZC3H13 inhibits the progression of colorectal cancer by suppressing the Ras-ERK pathway (Zhu et al., 2019[371]). ZC3H13 mediates m6A modification of PHF10 to induce a DNA damage response to promote pancreatic cancer that can be inhibited by fisetin (Huang et al., 2022[87]).

ZCCHC4 is a 28S rRNA specific m6A methyltransferase (Ren et al., 2019[199]), but there are few reports on its role in tumors. ZCCHC4 promotes chemotherapy resistance in hepatocellular carcinoma by disrupting DNA damage-induced apoptosis (Zhu et al., 2022[372]). Additionally, it facilitates the development of colorectal cancer via the ZCCHC4-LncRNA GHRLOS-KDM5D axis (Ma et al., 2019[169]).

Erasers

FTO was identified as the first m6A demethylase in 2011 (Jia et al., 2011[102]). FTO can bind to various RNAs, including mRNA, snRNA, and tRNA, and can demethylate the internal m6A and cap m6Am in mRNA (Wei et al., 2018[282]). In the past 5-10 years, research on the impact of FTO on cancer progression has begun to emerge. FTO promotes the tumorigenesis of hepatocellular carcinoma and suppresses tumor immunity (Chen et al., 2024[15]). FTO fosters the tumorigenesis of colorectal cancer by triggering the expression of SLC7A11/GPX4 (Qiao et al., 2024[195]). FTO promotes tumor progression in gastric cancer (Zeng et al., 2024[331]; Wu et al., 2024[295]), bladder cancer (Wu et al., 2024[290]), colorectal cancer (Qiao et al., 2024[195]), hepatocellular carcinoma (Chen et al., 2024[15]; Jiang et al., 2024[105]), lung cancer (Gao et al., 2023[58]), cervical cancer (Wang et al., 2023[242]), and pancreatic cancer (Tan et al., 2022[233]; Wang et al., 2023[269]). FTO exerted a tumor-suppressing effect in thyroid cancer (Huang et al., 2022[92]; Ji et al., 2022[98]) and cholangiocarcinoma (Gao et al., 2021[59]; Rong et al., 2019[202]). However, in prostatic cancer (Zhao et al., 2024[355]; Hu et al., 2024[82]), clear cell renal cell carcinoma (Xu et al., 2022[310]; Shen et al., 2022[208]; Strick et al., 2020[218]; Zhuang et al., 2019[378]), and breast cancer (Xu et al., 2020[309]; Ni et al., 2024[177]; Ou et al., 2022[182]; Yan et al., 2024[312]), FTO has a dual pro-cancer and anti-carcinogenic role, or the current role is controversial.

ALKBH5 is another m6A demethylase. The demethylation activity of ALKBH5 affects mRNA output and RNA metabolism, as well as the assembly of mRNA processing factors in nuclear spots (Zheng et al., 2013[358]). The role of ALKBH5 in cancer has been widely demonstrated, and it affects cancer progression by regulating various biological processes such as proliferation, migration, invasion, and metastasis (Wang et al., 2020[251]). Recent studies have found that ALKBH5 positively correlates with PD-L1 expression and macrophage infiltration and promotes non-small cell lung cancer progression by regulating tumor immunity through JAK2/p-STAT3 (Hua et al., 2024[85]). ALKBH5 reduces CD58 in gastric cancer cells through m6A methylation, activates the PD-1/PD-L1 axis, and ultimately induces immune escape from gastric cancer cells (Suo et al., 2024[228]). ALKBH5 drives immunosuppression by targeting AXIN2 to promote colorectal cancer (Zhai et al., 2023[333]). Furthermore, ALKBH5 promotes the progression of ovarian cancer (An and Duan, 2024[2]), colorectal cancer (Sun et al., 2024[221]), and lung adenocarcinoma (Tan et al., 2024[230]) by regulating macrophage polarization. The above suggests that ALKBH5 plays an important role in mediating tumor immunity and regulating the tumor microenvironment, and is an important potential target for immunotherapy of malignant tumors.

Readers

IGF2BP1/2/3 are members of the Insulin-like growth factor-2 mRNA-binding proteins (IGF2BPs) family, and IGF2BPs are a highly conserved family of RNA-binding proteins (Nielsen et al., 1999[179]; Zhu et al., 2023[374]). In 2018, Huang et al. demonstrated that IGF2BP1/2/3 act as new m6A reader family members, and that IGF2BPs contribute to the stability and translation of thousands of potential mRNA targets in an m6A-dependent manner, thereby affecting gene expression (Huang et al., 2018[91]). IGF2BPs are overexpressed in various cancers, and recent studies have found that IGF2BP1 interacts with RPS15 and promotes the development of esophageal squamous cell carcinoma by recognizing m6A modifications (Zhao et al., 2023[356]). IGF2BP2 promotes cell cycle progression in triple-negative breast cancer through recruitment of EIF4A1 (Xia et al., 2024[299]). IGF2BP3 binds the SENP1 3-UTR in an m6A manner and enhances SENP1 expression, which in turn exacerbates acute myeloid leukemia (Wen et al., 2024[285]).

YTHDF1/2/3 and YTHDC1/2 all contain YT521-B homology (YTH) structural domains (Nayler et al., 2000[176]; Hartmann et al., 1999[74]). The YTH structural domain is an RNA-binding structural domain specialized for m6A recognition (Zhang et al., 2010[353]; Zou and He, 2024[379]). YTHDF1 is the most abundant m6A reader, which promotes protein translation (Ren et al., 2023[200]). YTHDF1 exhibited carcinogenic effects in colorectal cancer (Chen et al., 2024[16]), esophageal cancer (Zhang et al., 2024[342]), breast cancer (Wang et al., 2024[267]), gastric cancer (Song et al., 2024[215]), gallbladder cancer (Chen et al., 2024[18]), non-small cell lung cancer (Sun et al., 2024[225]), hepatocellular carcinoma (Zhang et al., 2024[349]), and bladder cancer (Zhu et al., 2023[373]). YTHDF2 regulates RNA degradation (Chen et al., 2022[28]; Hsu et al., 2017[81]), and YTHDF2 is a oncogenic gene in most cancer types (Bai et al., 2023[3]; Jin et al., 2024[111]; Jiang et al., 2024[107]; Li et al., 2020[128]; Zhang et al., 2023[343]), however, it exerted both carcinogenic and anticarcinogenic effects in gastric cancer (Fang et al., 2023[55]; Ren et al., 2024[198]; Zhou et al., 2023[366]), hepatocellular carcinoma (Yang et al., 2023[319]; Wen et al., 2024[287]; Hou et al., 2019[78]; Zhong et al., 2019[360]), and pancreatic cancers (Tan et al., 2022[233]; Guo et al., 2020[66]). YTHDF3 enhances mRNA translation assisted by YTHDF1 (Ren et al., 2023[200]; Chang et al., 2020[13]; Shi et al., 2017[211]), which is currently less studied in the field of oncology, and acts as an oncogene similar to YTHDF1 (Chang et al., 2020[13]; Zhang et al., 2024[340]; Duan et al., 2024[53]). YTHDC1 regulates mRNA splicing by recruiting and modulating pre mRNA splicing factors, enabling it to enter the binding region of targeted mRNA, and mediate the nuclear export of methylated mRNA (Xiao et al., 2016[300]; Roundtree et al., 2017[204]). YTHDC2 can improve the translation efficiency of target mRNA and also reduce mRNA abundance (Hsu et al., 2017[81]; Wu et al., 2024[294]). YTHDC1/2 have carcinogenic and anticarcinogenic effects in different cancers (Yuan et al., 2022[328], 2023[327]; Tan et al., 2022[229]; Yan et al., 2023[311]; Hou et al., 2019[79]; Zhou and Wang, 2024[361]; Wang et al., 2021[249], 2022[250]).

HNRNPC, HNRNPG, and HNRNPA2B1 are members of the HNRNP proteins. HNRNP (heterogeneous nuclear ribonucleo protein) can participate in multiple RNA metabolic processes, and its most widely studied function is to participate in RNA splicing processes (Zhang et al., 2021[346]). HNRNPC mediates mRNA splicing, 3'-terminal processing, and translation (Huang et al., 2021[94]; Liu et al., 2015[154]). Recent studies have found that circPPAP2B promotes proliferation and metastasis of renal clear cell carcinoma through HNRNPC-dependent alternative splicing (Zheng et al., 2024[359]). HNRNPC also functions as an oncogene in other cancers (Huang et al., 2024[93]; Chen et al., 2024[20]; Lian et al., 2023[140]). HNRNPG uses the Arg-Gly-Gly (RGG) motif to selectively bind m6A-modified RNA and regulate selective splicing (Zhou et al., 2019[362]). Current studies have only found potential effects on endometrial cancer (Hirschfeld et al., 2015[77]). HNRNPA2B1 is a nuclear reader of m6A and mediates effects on primary microRNA processing and selective splicing (Alarcón et al., 2015[1]). HNRNPA2B1 is also an m6A reader that drives cancer progression (Wang et al., 2024[253]; Yu et al., 2024[325]; Jin et al., 2024[113]; Liu et al., 2022[148]).

FMRP is one of the readers of m6A, which may affect translation directly or through interaction with YTHDF proteins (Wang et al., 2014[274], 2015[276]; Zhang et al., 2018[339]; Hsu et al., 2019[80]). And FMRP can affect nuclear mRNA output by recognizing m6A-modified mRNAs (Hsu et al., 2019[80]). Research has found that METTL3 mediated m6A modified FMRP drives the progression of hepatocellular carcinoma (Fu et al., 2024[56]). PRRC2A is a newly discovered m6A reader in 2019 that regulates the stability of its target Olig2 mRNA by specifically binding methylated RNA through the GRE structural domain (Wu et al., 2019[292]). PRRC2A has not yet been reported to function as an m6A reader in cancer.

m6A Modification in Cancer

Studies in recent years have illustrated that m6A modifications are strongly associated with cancer progression. And m6A modification regulators affect cancer progression by regulating different signaling pathways (Figure 2(Fig. 2)). We analyzed the effects of m6A modifications on the occurrence and progression of different cancers, starting from different cancer types (Figure 3(Fig. 3)).

Breast Cancer

Breast cancer has been reported to have surpassed lung cancer as the most common cancer among women and is the leading cause of cancer-related deaths among women (Bray et al., 2024[9]). Majority of m6A modifications promote breast cancer occurrence and progression. METTL16 regulates the mRNA stability of FBXO5 via m6A modification, thereby promoting the malignant behavior of breast cancer (Wang et al., 2024[263]). YTHDF1 promotes osteolytic bone metastasis in breast cancer by inducing translation (Wang et al., 2024[267]). HNRNPA2B1 promotes breast cancer progression by regulating mRNA selective export (Jin et al., 2024[113]). In contrast, ZC3H13 was found to be a tumor suppressor gene in breast cancer (Gong et al., 2020[63]). In addition, METTL3, METTL14, and ALKBH5 have been reported in studies of promoting and inhibiting breast cancer, suggesting that they may play both oncogenic and anti-oncogenic roles in breast cancer (Gong et al., 2020[63]; Li et al., 2024[138]; Xu et al., 2023[308]; Wang et al., 2024[247]; Sun et al., 2020[224]; Woodcock et al., 2024[288]; Liu et al., 2022[149]).

Lung Cancer

Lung cancer remains the most commonly diagnosed cancer in the entire population (12.4 % of all cancers globally) and is the leading cause of cancer deaths (18.7 % of all cancers) (Bray et al., 2024[9]). m6A modifications are strongly associated with lung cancer progression and chemotherapy resistance. In lung cancer, the m6A writer METTL3 has been most widely and intensively studied. METTL3 can promote chemoresistance in small cell lung cancer by inducing mitochondrial autophagy (Sun et al., 2023[226]). HIF-1α drives smoking-induced non-small cell lung cancer progression by promoting cell proliferation through METTL3-regulated m6A modification (Yang et al., 2023[317]). However, it has been shown that METTL3 is downregulated in lung cancer tissues and inhibits the migration and invasive ability of lung cancer cells in a YTHDF1-dependent manner (Zhang et al., 2024[342]). Although METTL3 has been extensively studied in lung cancer, its expression and role in lung cancer are still controversial and further studies are needed in the future. In addition to METTL3, METTL14, ALKBH5, and YTHDF1/2 also exhibited both oncogenic and anti-oncogenic effects in lung cancer (Gao et al., 2023[58]; Hua et al., 2024[85]; Ji et al., 2024[101]; Li et al., 2022[125]; Sun et al., 2022[227]; Tsuchiya et al., 2021[237]; Dou et al., 2022[50]). Furthermore, we found that among the m6A readers, the IGF2BPs family was closely associated with pro-tumor progression in lung cancer (Sun et al., 2023[220]; Zhou et al., 2024[370]; Lin et al., 2023[147]), while YTHDC1/2 was a suppressor gene of lung cancer progression (Yuan et al., 2023[327]; Sun et al., 2020[223]), and may become therapeutic targets for lung cancer.

Thyroid Cancer

Thyroid cancer is the seventh most common cancer and the fifth most common in women, with three times the incidence in women than in men, but with a lower mortality rate (Bray et al., 2024[9]). Existing literature indicates that m6A modification regulators mainly play an anti-cancer role in thyroid cancer. ZC3H13 increased the m6A modification of hsa_circ_0101050 and inhibited its expression, which in turn inhibited thyroid cancer. ZC3H13 increases the m6A modification of hsa_circ_0101050 and inhibits its expression, thereby suppressing thyroid cancer (Lv et al., 2024[167]). Demethylase ALKBH5 reduces m6A modification of circNRIP1 and down-regulates its expression to inhibit glycolysis in thyroid cancer cells (Ji et al., 2023[100]). YTHDC2 inhibits proliferation and induces apoptosis in thyroid cancer cells by regulating CYLD-mediated inactivation of the Akt pathway (Zhou and Wang, 2024[361]). FTO inhibits glycolysis and growth of thyroid cancer cells by destabilizing APOE mRNA with m6A modification (Huang et al., 2022[92]). METTL16 attenuates lipid metabolism via m6A-mediated stabilization of SCD1 mRNA and thus inhibits thyroid cancer (Li et al., 2024[134]). In contrast, IGF2BP2/3 exerts oncogenic effect in thyroid cancer (Wang et al., 2024[268]; Panebianco et al., 2017[186]). However, METTL3 has oncogenic and anti-oncogenic roles in thyroid cancer (Ning et al., 2023[180]; Lin et al., 2022[144]).

Gastric Cancer

Data from 2022 show that there are more than 968,000 new cases of gastric cancer globally, the fifth highest incidence and mortality rate among all cancers (Bray et al., 2024[9]). It was found that m6A plays an important role in the progression of gastric cancer. m6A modification promotes the proliferation (Wu et al., 2024[295]; Li et al., 2024[137]; Xu et al., 2022[305]) and metastasis (Liu et al., 2022[159]; Wang et al., 2024[255]) of gastric cancer, inhibits cell ferroptosis (Niu et al., 2024[181]; Yang et al., 2022[314]) and apoptosis (Ci et al., 2024[35]), and promotes chemotherapy resistance (Wang et al., 2024[253]; Zhu et al., 2022[376]) and immune escape (Suo et al., 2024[228]; Tang et al., 2024[234]) in gastric cancer. m6A modification usually promotes gastric cancer progression. IGF2BP1 recognizes METTL3-mediated m6A modification of APAF1-binding lncRNA (ABL), which enhances ABL stability and thus promotes gastric cancer proliferation and chemoresistance (Wang et al., 2022[260]). METTL5 promotes NRF2 mRNA stability, which in turn inhibits ferroptosis and promotes immune escape in gastric cancer (Li et al., 2024[136]). Acetylated SRSF2 binds YTHDF1 pre-mRNA, leading to enhanced YTHDF1 exon 4 skipping, which stimulates GC cell proliferation and migration (Liu et al., 2024[156]). Among the available studies, only METTL14 among the m6A modification regulators showed complete tumor suppression in gastric cancer. METTL14 mediates m6A modification of circORC5 to inhibit gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis (Fan et al., 2022[54]). METTL14 also mediates m6A modification of circUGGT2 to inhibit gastric cancer progression and chemoresistance by regulating the miR-186-3p/MAP3K9 axis (Chen et al., 2024[29]). Unlike most m6A modification regulators, ALKBH5 (Suo et al., 2024[228]; Hu et al., 2022[83]; Wang et al., 2024[261]), IGF2BP1 (Xu et al., 2022[305]; Ding et al., 2024[47]), and YTHDF2 (Ren et al., 2024[198]; Yang et al., 2022[314]; Shen et al., 2020[210]) exhibit both oncogenic and anti-oncogenic effects in gastric cancer.

Colorectal Cancer

According to 2022 data, there were more than 1.9 million new cases of colorectal cancer and 904,000 deaths, and that colorectal cancer had the third highest incidence but the second highest mortality rate (Bray et al., 2024[9]). Similar to other tumors, the regulation of m6A modifications in colorectal cancer is equally diverse and complex, and almost all m6A modifiers promote colorectal carcinogenesis. Similar to other tumors, the regulation of m6A modifications in colorectal cancer is equally diverse and complex, and almost all m6A modifiers except METTL14, ZC3H13, METTL3, FTO, ALKBH5, and YTHDF2 promote colorectal carcinogenesis. METTL14 and ZC3H13 play important regulatory roles in inhibiting colorectal cancer proliferation and metastasis (Zhu et al., 2019[371]; Chen et al., 2020[27]; Yang et al., 2020[316]). METTL3 (Ouyang et al., 2024[184]; Jiang et al., 2024[108]; Deng et al., 2019[45]), FTO (Qiao et al., 2024[195]; Ye et al., 2023[322]), ALKBH5 (Zhai et al., 2023[333]; Ye et al., 2023[322]), and YTHDF2 (Qiao et al., 2024[195]; Chen et al., 2020[27]; Shen et al., 2023[207]) may have different mechanisms to exhibit oncogenic and anti-oncogenic roles in colorectal cancer.

Liver Cancer

Primary liver cancer consists mainly of hepatocellular carcinoma (75 %-85 %) and intrahepatic cholangiocarcinoma (10 %-15 %) (Bray et al., 2024[9]; de Martel et al., 2020[43]). The incidence of liver cancer has been steadily decreasing as the number of HBV and HCV positive people has declined and aflatoxin exposure has decreased, but liver cancer remains the third leading cause of cancer death after lung cancer and colorectal cancer (Bray et al., 2024[9]). Considerable research has been published on m6A modification in hepatocellular carcinoma, and m6A modifiers mainly act as oncogenic factors. In addition to ZC3H13 and METTL14, m6A writers have been shown to be oncogenic factors in liver cancer. METTL3-mediated m6A modification leads to the upregulation of TUG1, which interacts with YBX1 to promote the upregulation of PD-L1 and CD47 transcripts, ultimately regulating tumor immune escape (Xi et al., 2024[297]). METTL16 regulates SENP3 mRNA stability in an m6A-dependent manner, confers ferroptosis resistance and promotes tumor progression in hepatocellular carcinoma (Wang et al., 2024[252]). In contrast, m6A writers METTL14 and ZC3H13 inhibit liver cancer progression. USP48 is regulated by METTL14-induced m6A modification and stabilizes SIRT6 to attenuate hepatocellular carcinoma glycolysis and inhibit progression (Du et al., 2021[52]). ZC3H13 is lowly expressed in hepatocellular carcinoma and may be involved in transcriptional dysregulation or the JAK-STAT pathway to inhibit tumor migration and invasion (Wu et al., 2022[293]). m6A readers also act as oncogenic factors in liver cancer in addition to YTHDF2. YTHDF1 promotes stemness and treatment resistance in hepatocellular carcinoma by enhancing NOTCH1 expression (Zhang et al., 2024[349]). Positive functional loops of YTHDF3 and PFKL in glucose metabolism in hepatocellular carcinoma promote tumor proliferation and metastasis (Zhou et al., 2022[363]). Whereas the role of YTHDF2 and m6A erasers FTO and ALKBH5 in hepatocellular carcinoma remains unclear or different mechanisms exist to promote and suppress tumors (Chen et al., 2022[30], 2024[15]; Zhong et al., 2019[360]; Liao et al., 2023[142]; Liu et al., 2022[152]; Wang et al., 2023[271]).

Cholangiocarcinoma

According to different locations, cholangiocarcinoma is classified into intrahepatic, perihilar and distal cholangiocarcinoma, and has a lower incidence compared to hepatocellular carcinoma (Brindley et al., 2021[10]). The incidence of cholangiocarcinoma is increasing every year, but its global epidemiology varies widely (Montal et al., 2020[175]). m6A modification in cholangiocarcinoma remains understudied at present. The current study suggests that METTL proteins are closely related to the pro-carcinogenic effects of cholangiocarcinoma. METTL3 mediates m6A modification of circSLCO1B3 and promotes intrahepatic cholangiocarcinoma proliferation and metastasis via miR-502-5p/HOXC8/ SMAD3 axis (Li et al., 2024[129]). METTL5-mediated m6A modification of 18S rRNA promotes growth and metastasis of intrahepatic cholangiocarcinoma cells (Dai et al., 2023[41]). METTL16 regulates FGFR4 expression in cholangiocarcinoma cells through PRDM15 signaling and promotes tumor proliferation and progression (Liu et al., 2023[155]). In contrast METTL14-mediated m6A modification inhibits the MACF1/β-catenin pathway in cholangiocarcinoma, which in turn exerts tumor suppressor effects (Zhang et al., 2022[352]).

Prostate Cancer

Prostate cancer is the second most common cancer in the world, the most commonly diagnosed cancer in nearly two-thirds of men worldwide, and the fifth leading cause of cancer deaths in men (Bray et al., 2024[9]). In prostate cancer, METTL3 remains the most studied m6A modification regulators, and METTL3 mediates m6A modification of USP4 mRNA at A2696 to promote prostate cancer invasion and metastasis (Chen et al., 2021[31]). m6A reader also plays an important regulatory role in prostate cancer. YTHDF1/2/3 promote prostate cancer proliferation, invasion and metastasis and suppress anti-tumor immunity by different mechanisms (Li et al., 2020[128], 2022[132]; Duan et al., 2024[53]; Wang et al., 2024[277]). HNRNP proteins are also cancer promoters in prostate cancer. HNRNPA2B1 induces maturation of miR-25-3p/miR-93-5p to regulate TGF-β and FOXO pathways leading to prostate cancer progression (Qi et al., 2023[194]). HNRNPC suppresses tumor immunity by increasing Treg cell activation and suppressing CD8 T cells (Cheng et al., 2023[34]). In contrast to HNRNP proteins, IGF2BPs cause elevated overall R-loop levels, cell migration and growth inhibition in prostate cancers by preventing DNMT1 binding to the SEMA3F promoter (Ying et al., 2024[323]). However, it has also been shown that IGF2BP2 is recruited by circABCC4, enhances CCAR1 mRNA stability and activates the Wnt/β-catenin pathway to promote prostate cancer stemness and metastasis (Huang et al., 2023[86]).

Bladder Cancer

Bladder cancer is the ninth most commonly diagnosed cancer in the world and is far more common in men than in women, but even among women it is the sixth most common cancer and the ninth leading cause of cancer deaths (Bray et al., 2024[9]). Recent studies have shown that m6A writer WTAP and circ0008399 interactions promote MTC assembly and activity and cisplatin resistance in bladder cancer (Wei et al., 2021[283]). For METTL3, studies have shown that it and RBM15 synergistically mediate m6A modification of lncRNAs to promote malignant progression of bladder cancer (Huang et al., 2024[95]). Moreover, METTL3 promotes tumor proliferation in bladder cancer by accelerating the maturation of pri-miR221/222 in an m6A-dependent manner (Han et al., 2019[70]). However, other studies have shown that METTL3 overexpression enhances m6A modification of LINC01106 in bladder cancer cells and inhibits tumor progression (Liu et al., 2024[150]). m6A reader similarly regulates bladder cancer progression. IGF2BPs are pro-cancer factors in bladder cancer and promote tumor proliferation and metastasis (Xie et al., 2021[301]; Tan et al., 2024[232]; Lv et al., 2024[168]). Similar to the IGF2BPs family, YTHDF1/2/3 promote bladder cancer progression and suppress tumor immunity (Zhang et al., 2023[343]; Jin et al., 2019[112]; Qiu et al., 2024[196]). However, the study by Zeng et al. also found that YTHDF2 degrades DHCR7 mRNA and inhibits cholesterol synthesis and cAMP signaling, which in turn inhibits bladder cancer metastasis (Zeng et al., 2024[332]).

Esophageal Cancer

Esophageal cancer is the 11th most commonly diagnosed cancer and the 7th leading cause of cancer deaths worldwide (Bray et al., 2024[9]). METTL3 promotes the proliferation, invasion and metastasis of esophageal cancer by regulating the methionine cycle (Jin et al., 2024[115]), Wnt/β-catenin (Zhang et al., 2024[348]), EMT (Wu et al., 2024[289]), PI3K/AKT (Jia and Yu, 2024[103]), Notch (Han et al., 2021[69]) signaling pathways and glycolysis (Gao et al., 2023[60]). m6A reader IGF2BPs family members similarly contribute to the malignant progression of esophageal cancer. IGF2BP1 promotes translation of p38 MAPK pathway proteins by recognizing and directly binding to the mRNAs of MKK6 and MAPK14 (Zhao et al., 2023[356]). IGF2BP2 induces circRUNX1 with m6A modification and promotes esophageal cancer proliferation and metastasis via miR-449b-5p/FOXP3 axis (Wang et al., 2022[244]). And linc01305 was found to promote esophageal cancer progression by interacting with IGF2BP2 and IGF2BP3 (Huang et al., 2021[88]). HNRNP proteins are also cancer-promoting factors in esophageal cancer (Li et al., 2021[130]; Zhou et al., 2023[368]). Differently, YTHDF2 and METTL14 exhibit anticancer effects in esophageal cancer (Cui et al., 2021[38]; Liu et al., 2021[162]). Furthermore, YTHDF1 and ALKBH5 have dual roles of tumor promotion and tumor suppression in esophageal cancer (Zhang et al., 2024[342]; Cui et al., 2021[38]; Wu et al., 2022[291]; Chen et al., 2021[23]).

Cervical Cancer

Cervical cancer is the fourth most common cancer in terms of female morbidity and mortality, and globally it is the most common type of cancer in 25 countries and the most common cause of cancer-related deaths in 37 countries (Bray et al., 2024[9]). The study of m6A modifications in cervical cancer has gradually increased in recent years and has been found to act mainly as tumor promoters (Mao et al., 2023[170]). However, METTL3 and METTL14 have also been found to be both anti-oncogenic factors in cervical cancer. A study found that METTL3 can inhibit the survival ability of cervical cancer cells and increase cisplatin sensitivity (Li et al., 2021[135]). METTL14 enhances sorafenib-induced ferroptosis through the PI3K/Akt signaling pathway also inhibits cervical cancer (Li et al., 2024[131]).

Endometrial Cancer

Mortality from endometrial cancer has been on an upward trend since the mid-1990s and remains an important cause of cancer deaths in women (Siegel et al., 2022[214]). Up to now, there is still a relative paucity of explorations on m6A modifications in the field of endometrial cancer. It has been shown that m6A writers METTL3 inhibits the proliferation and migration of endometrial cancer cells and promotes the proliferation of CD8+ T cells (Zhan et al., 2023[334]). However, another study showed that METTL3 upregulates FGD5-AS1 expression through m6A modification, enhances chemoresistance in endometrial cancer cells, and promotes immune escape (Hao et al., 2024[73]). Similar to METTL3, WTAP exhibits both oncogenic and anti-oncogenic effects in endometrial cancer (Wang et al., 2024[243]; Li et al., 2021[133]). Differently, METTL14 decreases GPX4 mRNA stability through a YTHDF2-dependent mechanism, increases lipid peroxidation levels, and accelerates iron death in endometrial cancer, and thereby inhibits tumor progression (Wang et al., 2023[278]). m6A readers and erasers act primarily as tumor promoters in endometrial cancer. The IGF2BPs family was found to promote endometrial cancer progression by regulating cell proliferation and cancer cell stemness (Wang et al., 2024[243]; Zhang et al., 2021[344]; Shi et al., 2024[212]). For m6A erasers, it has been shown that FTO promotes endometrial cancer metastasis by activating the WNT signaling pathway (Zhang et al., 2021[345]). And ALKBH5 promotes endometrial cancer proliferation and invasion by eliminating the m6A modification of IGF1R (Pu et al., 2020[193]).

Ovarian Cancer

Ovarian cancer is the seventh most common cancer among women in the world and the gynecologic cancer with the highest mortality rate, with a survival rate of 46 % at five years after diagnosis (Lheureux et al., 2019[121]). Recent studies have found that m6A regulators function primarily as cancer promoting factors in ovarian cancer. METTL3 inhibits CCNG2 expression by promoting the maturation of pri-microRNA-1246, which promotes ovarian carcinogenesis and metastasis (Bi et al., 2021[7]). In addition to METTL3, m6A writers VIRMA and RBM15 function as oncogenes in ovarian cancer (Yuan et al., 2023[326]; Gan et al., 2023[57]). For m6A readers, the IGF2BPs family was found to promote proliferation, metastasis, and immune escape in ovarian cancer, which in turn promotes tumor progression (Wang et al., 2023[264], 2024[254]; Li et al., 2024[126]). YTHDF1/2 also promotes ovarian cancer progression by regulating mRNA stability of downstream target molecules (Liu et al., 2020[157]; Hao et al., 2021[72]; Xu et al., 2021[303]; Sun et al., 2023[222]). Furthermore, m6A erasers ALKBH5 promote ovarian cancer invasion, lymph node metastasis, and cisplatin resistance by regulating EMT, FAK, and JAK2/STAT3 signaling pathways (Sun et al., 2023[222]; Xu et al., 2024[307]; Nie et al., 2021[178]). Contrary to the above effects, METTL16, YTHDC1, and FTO all exert anti-oncogenic effects in ovarian cancer (Li et al., 2023[124]; Wang et al., 2023[272]; Huang et al., 2020[90]).

Pancreatic Cancer

With 511,000 new cases and 467,000 deaths in 2022, pancreatic cancer ranks sixth in cancer-related mortality and has one of the worst prognoses among malignant tumors (Bray et al., 2024[9]). In pancreatic cancer research, m6A modifications have been found to play a key tumor-promoting role. m6A modifications have been found to promote proliferation (Jin et al., 2024[114]; Chen et al., 2023[19]; Hu et al., 2022[84]), metastasis (Zhou et al., 2023[369]; Deng et al., 2021[44]), stem cell-like properties (Jin et al., 2024[114]; Chen et al., 2023[19]; Ouyang et al., 2024[183]), and chemotherapy resistance (Ouyang et al., 2024[183]; Lin et al., 2023[143]; Su et al., 2023[219]) in pancreatic cancer. m6A writers METTL3 mediates cigarette smoke-induced m6A modification of miR-25-3p, leading to activation of oncogenic AKT-p70S6K signaling in pancreatic cancer (Zhang et al., 2019[341]). METTL5 promotes c-Myc translation leading to pancreatic cancer progression (Huang et al., 2022[89]). METTL14 leads to decreased PERP levels through m6A modification, which in turn promotes pancreatic cancer proliferation and metastasis (Wang et al., 2020[258]). WTAPP1 binds WTAP mRNA and recruits the EIF3 translation initiation complex to promote WTAP translation, which enhances the activation of Wnt signaling and ultimately triggers the malignant phenotype of pancreatic cancer (Deng et al., 2021[44]). In addition, ZC3H13 and RBM15 also promote pancreatic cancer progression by regulating DNA damage repair and tumor immune infiltration in pancreatic cancer (Huang et al., 2022[87]; Wang et al., 2024[270]). Similarly, the m6A reader IGF2BPs family and YTHDF proteins also play a role in promoting pancreatic cancer through different pathways (Jin et al., 2024[114]; Hu et al., 2022[84]; Lin et al., 2023[143]; Wan et al., 2019[241]; Peng et al., 2023[190]; Chen et al., 2024[22]). And for m6A erasers, FTO mediates m6A modification of PDGFC and stabilizes its expression, leading to reactivation of the Akt signaling pathway and promoting pancreatic cancer cell growth (Tan et al., 2022[233]). In contrast, ALKBH5 prevents pancreatic cancer progression in an m6A-dependent manner by a different mechanism (Guo et al., 2020[66]; Zhang et al., 2022[351]; He et al., 2021[75]).

Head and Neck Cancer

Approximately 90 % of head and neck cancer cases are head and neck squamous cell carcinoma (Liu et al., 2024[160]), with data for 2022 reporting 946,456 new cases and 482,001 deaths (Bray et al., 2024[9]), suggesting that it remains an important cause of cancer deaths. METTL3 enhances the stability and upregulates the expression of CDC25B mRNA, which activates the G2/M phase of the cell cycle and leads to malignant progression of head and neck squamous cell carcinoma (Guo et al., 2022[67]). METTL3 also promotes BMI1 translation in an IGF2BP1-dependent manner, which in turn promotes proliferation and metastasis in oral squamous cell carcinoma (Liu et al., 2020[153]). RBM15-mediated IGF2BP3-dependent m6A modification enhances TMBIM6 stability and leads to laryngeal squamous cell carcinoma progression (Wang et al., 2021[275]). METTL14 is recruited by RASAL2-AS1 and promotes the expression of LIS1, which in turn promotes the progression of head and neck squamous cell carcinoma (Rong et al., 2024[201]). IGF2BPs has also been found to play a promotional role in head and neck cancer. IGF2BP1 and IGF2BP3 are involved in recognition and stabilization of m6A-tagged HOXC10 mRNA leading to head and neck squamous cell carcinoma growth and metastasis (Zhou et al., 2024[367]). IGF2BP3 also regulates autophagy and promotes laryngeal squamous cell carcinoma progression by activating the TMA7-UBA2-PI3K pathway (Yang et al., 2023[315]). IGF2BP2 is activated by KLF7-regulated super-enhancer-driven transcription and promotes malignant progression in head and neck squamous cell carcinoma (Cai et al., 2024[11]). However, Liang et al. demonstrated that METTL14 inhibited oral squamous cell carcinoma progression by post-transcriptionally enhancing RB1CC1 expression in an IGF2BP2-dependent manner (Liang et al., 2023[141]).

Leukemia

Leukemias are a group of cancers of the hematopoietic system that are the 11th most prevalent cancer and the 10th leading cause of cancer deaths worldwide (Miranda-Filho et al., 2018[173]). Published studies have demonstrated that m6A modifiers all exhibit pro-oncogenic effects in leukemia. Professor Kouzarides' team at the University of Cambridge discovered in 2017 that METTL3 is recruited by CEBPZ into the promoters of specific genes, leading to an increase in translation of genes such as SP1 to promote cell growth in acute myeloid leukemia (Barbieri et al., 2017[4]). In 2021, the team further demonstrated the effectiveness of using the highly efficient METTL3 inhibitor STM2457 to treat acute myeloid leukemia (Yankova et al., 2021[320]). METTL16 has also been found to exert its oncogenic effects by reprogramming branched-chain amino acid metabolism in acute myeloid leukemia (Han et al., 2023[71]). Wang et al. and Shen et al. also demonstrated that ALKBH5 is required for the development of acute myeloid leukemia and maintenance of leukemic stem cell function (Shen et al., 2020[206]; Wang et al., 2020[248]). Similarly, the m6A eraser FTO was found to act as an oncogenic agent in acute myeloid leukemia in 2017 (Li et al., 2017[139]), and the small molecule inhibitors FB23 and FB23-2 were found to inhibit the proliferation of acute myeloid leukemia cells in vitro and in vivo in 2019 (Huang et al., 2019[96]).

Kidney Cancer

Kidney cancer is the 9th most common cancer in men and the 14th most common cancer in women, with clear cell carcinoma of the kidney being the most common (Stewart et al., 2022[217]), and the incidence of kidney cancer continues to increase at an annual rate of 1.5 % (Siegel et al., 2024[213]). The study of m6A modification in kidney cancer has increased significantly in recent years. Aberrant activation of FTO sensitizes renal clear cell carcinoma to BRD9 inhibitors (Zhang et al., 2021[336]), and FTO inhibits clear cell renal cell carcinoma through the PGC-1α signaling axis (Zhuang et al., 2019[378]). However, recent studies have also found that FTO-mediated autophagy promotes the progression of clear cell renal cell carcinoma by regulating SIK2 mRNA stability (Xu et al., 2022[310]). This implies that the role of FTO in clear cell renal cell carcinoma needs to be further investigated in depth. IGF2BP1/3 also found to promote kidney cancer progression. IGF2BP1 interacts with LINC01426 to regulate the CTBP1/miR-423-5p/FOXM1 axis and thus promotes clear cell renal cell carcinoma progression (Jiang et al., 2021[110]). IGF2BP3 stable LncRNA CDKN2B-AS1 drives malignancy in renal clear cell carcinoma through activation of NUF2 transcription (Xie et al., 2021[302]). In contrast, IGF2BP2 acts as a tumor suppressor in kidney cancer (Pan et al., 2022[185]; Ren et al., 2024[197]). YTHDF proteins also function as a tumor suppressor in kidney cancer (Liu et al., 2022[161]; Li et al., 2022[122]; Dai et al., 2024[40]).

Melanoma

The incidence of melanoma is increasing by 2-3 % per year from 2015-2019 (Siegel et al., 2024[213]). 100,640 new diagnoses of cutaneous melanoma and 8,290 deaths are expected globally in 2014 (Siegel et al., 2024[213]). Recent studies have found that METTL3 localizes to mRNAs for m6A modification with the help of DHPS to drive melanoma (Guo et al., 2024[65]). ALKBH5 promotes cutaneous melanoma by mediating the downregulation of ABCA1 expression in an m6A-dependent manner (Wang et al., 2024[246]). METTL14 mediates m6A modification of RUNX2 to activate the Wnt/β-catenin signaling pathway and promote choroidal melanoma migration and invasion (Zhang et al., 2022[350]). However, a recent study published the opposite view, that METTL14 exerts tumor suppression in ocular melanoma by promoting the expression of the tumor suppressor FAT4 in a YTHDF1-dependent manner (Zhuang et al., 2023[377]). Furthermore, in 2024 Han et al. designed RM3, a peptide inhibitor specifically targeting the METTL 3/14 complex, which showed inhibitory effects on a variety of melanoma cell lines and exhibited a lower IC50 compared to STM2457 (Yankova et al., 2021[320]; Han et al., 2024[68]).

Glioblastoma

Glioblastoma is the most common brain tumor, accounting for 45-50 % of all primary malignant brain tumors, and has a very poor prognosis (Grabiec et al., 2024[64]). Currently m6A modifications in glioblastoma are understudied and controversial. METTL3 has been found to promote glioblastoma proliferation and self-renewal induced by PDGF signaling (Lv et al., 2022[166]). Moreover, METTL3 and YTHDF1 can directly target ADAR1 transcripts, leading to elevated expression and tumor-promoting effects in glioblastoma (Tassinari et al., 2021[235]). On the contrary, the view of another study suggests that overexpression of METTL3 inhibits the growth and self-renewal of glioblastoma (Cui et al., 2017[37]).

In 2017, m6A demethylase ALKBH5 was found to promote tumorigenicity of glioblastoma stem-like cells by maintaining FOXM1 expression (Zhang et al., 2017[347]). Subsequent studies have also found that ALKBH5 and USP36 interact to maintain stem cell properties in glioblastoma and promote tumor progression (Chang et al., 2023[14]). The IGF2BPs family plays a pro-carcinogenic role by regulating glioma occurrence, progression and temozolomide resistance (Wang et al., 2015[265]; Cun et al., 2023[39]; Zhang et al., 2023[354]; Li et al., 2022[123]). Yet another study indicated that IGF2BP1 stabilizes circSPECC1 expression and promotes its encoding of the SPECC1-415aa protein to inhibit proliferation and metastasis of glioblastoma cells (Wei et al., 2024[281]). In addition, YTHDF protein is also a pro-carcinogenic factor for glioblastoma (Yarmishyn et al., 2020[321]; Dixit et al., 2021[48]; Lee et al., 2023[117]).

Osteosarcoma

Osteosarcoma is the most common primary malignant bone tumor, with the highest incidence in children, adolescents, and the elderly population >60 years of age (Beird et al., 2022[5]). Five-year survival rate for patients with metastatic osteosarcoma is <20 % (Gill and Gorlick, 2021[61]). m6A writers positively regulate malignant progression in osteosarcoma. METTL3-mediated m6A modification of LINC00520 promotes glycolysis and resistance to cisplatin in osteosarcoma by inhibiting ubiquitination of ENO1 (Wei et al., 2024[284]). METTL14-mediated methylation enhances the translational efficiency of MN1 and promotes osteosarcoma progression and chemoresistance to all-trans retinoic acid (Li et al., 2022[127]). METTL16, WTAP, VIRMA and RBM15 also positively regulate osteosarcoma proliferation, invasion and migration by regulating PI3K/AKT, JAK2/STAT3 and aerobic glycolysis pathways (Cheng et al., 2024[32]; Chen et al., 2020[24]; Luo et al., 2023[163]; Yang et al., 2023[313]).

Other Cancers

Gallbladder cancer is a common malignant tumor of the gastrointestinal tract characterized by high aggressiveness (Piovani et al., 2024[192]). In gallbladder cancer, m6A modification of TRPM2-AS by METTL3/14 is recognized by IGF2BP2 and promotes tumor angiogenesis through activation of the NOTCH1 signaling pathway (He et al., 2024[76]). Retinoblastoma is a childhood retinal cancer with about 8,000 cases worldwide (Cobrinik, 2024[36]). YTHDF1 promotes retinoblastoma growth by binding to and enhancing the stability of mRNAs from multiple oncogenes (Luo et al., 2023[165]). In lymphoma, YTHDF2 promotes tumorigenesis in diffuse large B-cell lymphoma by regulating ACER2-mediated ceramide metabolism in an m6A-dependent manner (Chen et al., 2024[25]). Tumorigenicity due to the interaction of the m6A reader YTHDC1 and the RNA helicase DDX5 has been identified in rhabdomyosarcoma (Dattilo et al., 2023[42]). VIRMA promotes proliferation, migration, invasion and chemoresistance to cisplatin in germ cell tumors (Miranda-Gonçalves et al., 2021[174]). METTL3 induces c-MYC expression in thymic epithelial tumor to promote tumor proliferation (Iaiza et al., 2021[97]).

Recent Advances and Future Directions

Since the first discovery of m6A modification in the 1970s, a large number of studies targeting m6A have emerged, especially in the field of cancer. Currently, m6A modifications have been shown to regulate cancer occurrence and development by modulating different target molecules. Although m6A modifications have been shown to be involved in the biological processes of cancer, their role in cancer is not yet fully sufficient. Of particular note, current reports in the literature show that m6A modification regulators have both tumorigenic and anti-tumorigenic effects in the same tumor, or that their effects in cancer are controversial. The reason for this may be that m6A modification regulators mediate different downstream mechanisms by regulating the transcripts of different genes, which ultimately exert both oncogenic and anti-oncogenic effects in the same tumor. However, this controversy has somewhat interfered and hindered subsequent studies of m6A modifications in tumors. In response to this situation, future researchers need to study the epigenetic modification network of the m6A regulatory process in greater depth to provide clearer targets for targeted tumor therapy.

In recent years, as m6A modification research in the field of human cancer is increasing, more and more evidence indicates the feasibility of targeting m6A modification regulators and its potential to become an alternative therapy for cancer chemotherapy resistance (Zhou et al., 2023[365]). In 2019, Professor Yang's team at the University of Chinese Academy of Sciences discovered the significant inhibitory effect of the FTO inhibitor FB23-2 on the proliferation of human acute myeloid leukemia cells (Huang et al., 2019[96]). Professor Kouzarides' team at the University of Cambridge has demonstrated the efficacy of STM2457, a small molecule inhibitor of METTL3, in treating acute myeloid leukemia in 2021 (Yankova et al., 2021[320]). In 2024, Professor Shi's team at Hunan University in China designed a peptide inhibitor that specifically targets the METTL 3/14 complex, showing inhibitory effects on multiple melanoma cell lines (Han et al., 2024[68]). Although these advances are encouraging, no drugs targeting m6A modification regulators have yet entered clinical trials, but there is no denying that these discoveries lay the groundwork for targeting m6A modifications for the treatment of human cancers in the future. We believe that more extensive and in-depth exploration of the mechanism of m6A regulation of human cancers will be carried out in the future and provide better m6A therapeutic targets and facilitate the generation of more effective targeted therapeutic drugs.

Conclusions

This paper reviews the biological regulation of m6A modification regulators in human cancers. m6A modification regulators can regulate oncogene/anti-oncogene expression, cancer occurrence, cancer cell proliferation, invasion, migration, angiogenesis, cancer cell stemness, and chemoresistance to regulate cancer progression. The existing problem is that the research on m6A modification in cancer is not sufficient, and its deeper regulatory mechanism in cancer and the crosstalk of various m6A modification regulators in cancer are not yet fully understood.

In addition, although effective small molecule compounds targeting m6A modification regulators have emerged, more studies are needed to demonstrate the clinical efficacy of targeting m6A modifications.

Notes

Liang Shang, Feng Cao (Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China; E-mail: f.cao@xwhosp.org) and Fei Li (Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, China; E-mail: feili36@ccmu.edu.cn) contributed equally as corresponding author.

Declaration

Ethics approval and consent to participate

Not applicable.

Consent for publication

All authors gave their consent for publication.

Availability of data and materials

Not applicable.

Competing interests

No authors have any conflict of interest or competing interests to declare.

Funding

This work was supported by the National Natural Science Foundation of China (82470678), Beijing Natural Science Foundation (7242069), Beijing Hospital Administration Training Project (PX2023030), and Capital Medical Development and Research Special Project (Z201100005520090).

Author contributions

X.X and Z.F retrieved articles and wrote the manuscript. H.Z, Z.W, J.L and Y.J drawn figure and table. L.S, F.C and F.L supervised this manuscript. All authors read and approved the final manuscript.

Acknowledgments

None.

 

References

1. Alarcón CR, Goodarzi H, Lee H, Liu X, Tavazoie S, Tavazoie SF. HNRNPA2B1 Is a Mediator of m(6)A-Dependent Nuclear RNA Processing Events. Cell. 2015;162:1299-308. doi: 10.1016/j.cell.2015.08.011
2. An Y, Duan H. ALKBH5 modulates macrophages polarization in tumor microenvironment of ovarian cancer. J Ovarian Res. 2024;17(1):84. doi: 10.1186/s13048-024-01394-4
3. Bai X, Chen J, Zhang W, Zhou S, Dong L, Huang J, et al. YTHDF2 promotes gallbladder cancer progression and gemcitabine resistance via m6A-dependent DAPK3 degradation. Cancer Sci. 2023;114:4299-313. doi: 10.1111/cas.15953
4. Barbieri I, Tzelepis K, Pandolfini L, Shi J, Millán-Zambrano G, Robson SC, et al. Promoter-bound METTL3 maintains myeloid leukaemia by m6A-dependent translation control. Nature. 2017;552(7683):126-31. doi: 10.1038/nature24678
5. Beird HC, Bielack SS, Flanagan AM, Gill J, Heymann D, Janeway KA, et al. Osteosarcoma. Nat Rev Dis Primers. 2022;8(1):77. doi: 10.1038/s41572-022-00409-y
6. Bhattarai PY, Kim G, Lim S-C, Choi HS. METTL3-STAT5B interaction facilitates the co-transcriptional m6A modification of mRNA to promote breast tumorigenesis. Cancer Lett. 2024;603:217215. doi: 10.1016/j.canlet.2024.217215
7. Bi X, Lv X, Liu D, Guo H, Yao G, Wang L, et al. METTL3 promotes the initiation and metastasis of ovarian cancer by inhibiting CCNG2 expression via promoting the maturation of pri-microRNA-1246. Cell Death Discov. 2021;7(1):237. doi: 10.1038/s41420-021-00600-2
8. Bokar JA, Shambaugh ME, Polayes D, Matera AG, Rottman FM. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997;3:1233-47
9. Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229-63. doi: 10.3322/caac.21834
10. Brindley PJ, Bachini M, Ilyas SI, Khan SA, Loukas A, Sirica AE, et al. Cholangiocarcinoma. Nat Rev Dis Primers. 2021;7(1):65. doi: 10.1038/s41572-021-00300-2
11. Cai H, Liang J, Jiang Y, Wang Z, Li H, Wang W, et al. KLF7 regulates super-enhancer-driven IGF2BP2 overexpression to promote the progression of head and neck squamous cell carcinoma. J Exp Clin Cancer Res. 2024;43(1):69. doi: 10.1186/s13046-024-02996-y
12. Cesaro B, Iaiza A, Piscopo F, Tarullo M, Cesari E, Rotili D, et al. Enhancing sensitivity of triple-negative breast cancer to DNA-damaging therapy through chemical inhibition of the m6A methyltransferase METTL3. Cancer Commun (Lond). 2024;44:282-6. doi: 10.1002/cac2.12509
13. Chang G, Shi L, Ye Y, Shi H, Zeng L, Tiwary S, et al. YTHDF3 induces the translation of m6a-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell. 2020;38:857-71.e7. doi: 10.1016/j.ccell.2020.10.004
14. Chang G, Xie GS, Ma L, Li P, Li L, Richard HT. USP36 promotes tumorigenesis and drug sensitivity of glioblastoma by deubiquitinating and stabilizing ALKBH5. Neuro Oncol. 2023;25:841-53. doi: 10.1093/neuonc/noac238
15. Chen A, Zhang VX, Zhang Q, Sze KM-F, Tian L, Huang H, et al. Targeting the oncogenic m6A demethylase FTO suppresses tumourigenesis and potentiates immune response in hepatocellular carcinoma. Gut. 2024;74(1):90-102. doi: 10.1136/gutjnl-2024-331903
16. Chen D, Ji F, Zhou Q, Cheung H, Pan Y, Lau HCH, et al. RUVBL1/2 blockade targets YTHDF1 activity to suppress m6a-dependent oncogenic translation and colorectal tumorigenesis. Cancer Res. 2024;84:2856-72. doi: 10.1158/0008-5472.CAN-23-2081
17. Chen H, Gu L, Orellana EA, Wang Y, Guo J, Liu Q, et al. METTL4 is an snRNA m6Am methyltransferase that regulates RNA splicing. Cell Res. 2020;30:544-7. doi: 10.1038/s41422-019-0270-4
18. Chen J, Bai X, Zhang W, Yan Z, Liu Y, Zhou S, et al. YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis. J Cell Mol Med. 2024;28(9):e18328. doi: 10.1111/jcmm.18328
19. Chen J, Zhang H, Xiu C, Gao C, Wu S, Bai J, et al. METTL3 promotes pancreatic cancer proliferation and stemness by increasing stability of ID2 mRNA in a m6A-dependent manner. Cancer Lett. 2023;565:216222. doi: 10.1016/j.canlet.2023.216222
20. Chen J-J, Lu T-Z, Wang T, Yan W-H, Zhong F-Y, Qu X-H, et al. The m6A reader HNRNPC promotes glioma progression by enhancing the stability of IRAK1 mRNA through the MAPK pathway. Cell Death Dis. 2024;15(6):390. doi: 10.1038/s41419-024-06736-0
21. Chen K, Lu Z, Wang X, Fu Y, Luo G-Z, Liu N, et al. High-resolution N(6) -methyladenosine (m(6) A) map using photo-crosslinking-assisted m(6) A sequencing. Angew Chem Int Ed Engl. 2015;54:1587-90. doi: 10.1002/anie.201410647
22. Chen K, Wang Y, Dai X, Luo J, Hu S, Zhou Z, et al. FBXO31 is upregulated by METTL3 to promote pancreatic cancer progression via regulating SIRT2 ubiquitination and degradation. Cell Death Dis. 2024;15(1):37. doi: 10.1038/s41419-024-06425-y
23. Chen P, Li S, Zhang K, Zhao R, Cui J, Zhou W, et al. N6-methyladenosine demethylase ALKBH5 suppresses malignancy of esophageal cancer by regulating microRNA biogenesis and RAI1 expression. Oncogene. 2021;40(37):5600-12. doi: 10.1038/s41388-021-01966-4
24. Chen S, Li Y, Zhi S, Ding Z, Wang W, Peng Y, et al. WTAP promotes osteosarcoma tumorigenesis by repressing HMBOX1 expression in an m6A-dependent manner. Cell Death Dis. 2020;11(8):659. doi: 10.1038/s41419-020-02847-6
25. Chen X, Lu T, Ding M, Cai Y, Yu Z, Zhou X, et al. Targeting YTHDF2 inhibits tumorigenesis of diffuse large B-cell lymphoma through ACER2-mediated ceramide catabolism. J Adv Res. 2024;63:17-33. doi: 10.1016/j.jare.2023.10.010
26. Chen X, Wang M, Wang H, Yang J, Li X, Zhang R, et al. METTL3 inhibitor suppresses the progression of prostate cancer via IGFBP3/AKT pathway and synergizes with PARP inhibitor. Biomed Pharmacother. 2024;179:117366. doi: 10.1016/j.biopha.2024.117366
27. Chen X, Xu M, Xu X, Zeng K, Liu X, Pan B, et al. METTL14-mediated N6-methyladenosine modification of SOX4 mRNA inhibits tumor metastasis in colorectal cancer. Mol Cancer. 2020;19(1):106. doi: 10.1186/s12943-020-01220-7
28. Chen X, Zhou X, Wang X. m6A binding protein YTHDF2 in cancer. Exp Hematol Oncol. 2022;11(1):21. doi: 10.1186/s40164-022-00269-y
29. Chen X-Y, Yang Y-L, Yu Y, Chen Z-Y, Fan H-N, Zhang J, et al. CircUGGT2 downregulation by METTL14-dependent m6A modification suppresses gastric cancer progression and cisplatin resistance through interaction with miR-186-3p/MAP3K9 axis. Pharmacol Res. 2024;204:107206. doi: 10.1016/j.phrs.2024.107206
30. Chen Y, Ling Z, Cai X, Xu Y, Lv Z, Man D, et al. Activation of YAP1 by N6-Methyladenosine-Modified circCPSF6 Drives Malignancy in Hepatocellular Carcinoma. Cancer Res. 2022;82(4):599-614. doi: 10.1158/0008-5472.CAN-21-1628
31. Chen Y, Pan C, Wang X, Xu D, Ma Y, Hu J, et al. Silencing of METTL3 effectively hinders invasion and metastasis of prostate cancer cells. Theranostics. 2021;11:7640-57. doi: 10.7150/thno.61178
32. Cheng J, Xu Z, Tan W, He J, Pan B, Zhang Y, et al. METTL16 promotes osteosarcoma progression by downregulating VPS33B in an m6 A-dependent manner. J Cell Physiol. 2024;239(3):e31068. doi: 10.1002/jcp.31068
33. Cheng X, Yang H, Chen Y, Zeng Z, Liu Y, Zhou X, et al. METTL3-mediated m6A modification of circGLIS3 promotes prostate cancer progression and represents a potential target for ARSI therapy. Cell Mol Biol Lett. 2024;29(1):109. doi: 10.1186/s11658-024-00628-z
34. Cheng Y, Li L, Wei X, Xu F, Huang X, Qi F, et al. HNRNPC suppresses tumor immune microenvironment by activating Treg cells promoting the progression of prostate cancer. Cancer Sci. 2023;114:1830-45. doi: 10.1111/cas.15745
35. Ci Y, Zhang Y, Zhang X. Methylated lncRNAs suppress apoptosis of gastric cancer stem cells via the lncRNA-miRNA/protein axis. Cell Mol Biol Lett. 2024;29(1):51. doi: 10.1186/s11658-024-00568-8
36. Cobrinik D. Retinoblastoma origins and destinations. N Engl J Med. 2024;390:1408-19. doi: 10.1056/NEJMra1803083
37. Cui Q, Shi H, Ye P, Li L, Qu Q, Sun G, et al. m6A RNA Methylation Regulates the Self-Renewal and Tumorigenesis of Glioblastoma Stem Cells. Cell Rep. 2017;18:2622-34. doi: 10.1016/j.celrep.2017.02.059
38. Cui Y, Zhang C, Ma S, Li Z, Wang W, Li Y, et al. RNA m6A demethylase FTO-mediated epigenetic up-regulation of LINC00022 promotes tumorigenesis in esophageal squamous cell carcinoma. J Exp Clin Cancer Res. 2021;40(1):294. doi: 10.1186/s13046-021-02096-1
39. Cun Y, An S, Zheng H, Lan J, Chen W, Luo W, et al. Specific regulation of m6A by SRSF7 promotes the progression of glioblastoma. Genom Proteom Bioinform. 2023;21:707-28. doi: 10.1016/j.gpb.2021.11.001
40. Dai C, Cao J, Tang Y, Jiang Y, Luo C, Zheng J. YTHDF3 phase separation regulates HSPA13-dependent clear cell renal cell carcinoma development and immune evasion. Cancer Sci. 2024;115:2588-601. doi: 10.1111/cas.16228
41. Dai Z, Zhu W, Hou Y, Zhang X, Ren X, Lei K, et al. METTL5-mediated 18S rRNA m6A modification promotes oncogenic mRNA translation and intrahepatic cholangiocarcinoma progression. Mol Ther. 2023;31:3225-42. doi: 10.1016/j.ymthe.2023.09.014
42. Dattilo D, Di Timoteo G, Setti A, Giuliani A, Peruzzi G, Beltran Nebot M, et al. The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs. Nat Commun. 2023;14(1):1898. doi: 10.1038/s41467-023-37578-7
43. de Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020;8(2):e180-90. doi: 10.1016/S2214-109X(19)30488-7
44. Deng J, Zhang J, Ye Y, Liu K, Zeng L, Huang J, et al. N6 -methyladenosine-mediated upregulation of WTAPP1 promotes WTAP translation and Wnt signaling to facilitate pancreatic cancer progression. Cancer Res. 2021;81:5268-83. doi: 10.1158/0008-5472.CAN-21-0494
45. Deng R, Cheng Y, Ye S, Zhang J, Huang R, Li P, et al. m6A methyltransferase METTL3 suppresses colorectal cancer proliferation and migration through p38/ ERK pathways. Onco Targets Ther. 2019;12:4391-402. doi: 10.2147/OTT.S201052
46. Desrosiers R, Friderici K, Rottman F. Identification of methylated nucleosides in messenger RNA from Novikoff hepatoma cells. Proc Natl Acad Sci U S A. 1974;71:3971-5
47. Ding N, Cao G, Wang Z, Xu S, Chen W. Tumor suppressive function of IGF2BP1 in gastric cancer through decreasing MYC. Cancer Sci. 2024;115:427-38. doi: 10.1111/cas.16047
48. Dixit D, Prager BC, Gimple RC, Poh HX, Wang Y, Wu Q, et al. The RNA m6A reader ythdf2 maintains oncogene expression and is a targetable dependency in glioblastoma stem cells. Cancer Discov. 2021;11:480-99. doi: 10.1158/2159-8290.CD-20-0331
49. Dong H, Zhang H, Mao X, Liu S, Xu W, Zhang Y. RBM15 promates the proliferation, migration and invasion of pancreatic cancer cell lines. Cancers (Basel). 2023;15(4):1084. doi: 10.3390/cancers15041084
50. Dou X, Wang Z, Lu W, Miao L, Zhao Y. METTL3 promotes non-small cell lung cancer (NSCLC) cell proliferation and colony formation in a m6A-YTHDF1 dependent way. BMC Pulm Med. 2022;22(1):324. doi: 10.1186/s12890-022-02119-3
51. Doxtader KA, Wang P, Scarborough AM, Seo D, Conrad NK, Nam Y. Structural basis for regulation of METTL16, an S-adenosylmethionine homeostasis factor. Mol Cell. 2018;71:1001-11.e4. doi: 10.1016/j.molcel.2018.07.025
52. Du L, Li Y, Kang M, Feng M, Ren Y, Dai H, et al. USP48 Is upregulated by Mettl14 to attenuate hepatocellular carcinoma via regulating SIRT6 stabilization. Cancer Res. 2021;81:3822-34. doi: 10.1158/0008-5472.CAN-20-4163
53. Duan J, Fan D, Chen P, Xiang J, Xie X, Peng Y, et al. YTHDF3 regulates the degradation and stability of m6a-enriched transcripts to facilitate the progression of castration-resistant prostate cancer. J Pineal Res. 2024;76(5):e13003. doi: 10.1111/jpi.13003
54. Fan H-N, Chen Z-Y, Chen X-Y, Chen M, Yi Y-C, Zhu J-S, et al. METTL14-mediated m6A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Mol Cancer. 2022;21(1):51. doi: 10.1186/s12943-022-01521-z
55. Fang Y, Wu X, Gu Y, Shi R, Yu T, Pan Y, et al. LINC00659 cooperated with ALKBH5 to accelerate gastric cancer progression by stabilising JAK1 mRNA in an m6 A-YTHDF2-dependent manner. Clin Transl Med. 2023;13(3):e1205. doi: 10.1002/ctm2.1205
56. Fu S, Sun D, Wang Z, Zhu P, Ding W, Huang J, et al. METTL3-Mediated m6A modification of FMRP drives hepatocellular carcinoma progression and indicates poor prognosis. Cancer Biother Radiopharm. 2024;39:745-54. doi: 10.1089/cbr.2023.0186
57. Gan L, Zhao S, Gao Y, Qi Y, Su M, Wang A, et al. N6-methyladenosine methyltransferase KIAA1429 promoted ovarian cancer aerobic glycolysis and progression through enhancing ENO1 expression. Biol Direct. 2023;18(1):64. doi: 10.1186/s13062-023-00420-7
58. Gao L, Wang A, Chen Y, Cai X, Li Y, Zhao J, et al. FTO facilitates cancer metastasis by modifying the m6A level of FAP to induce integrin/FAK signaling in non-small cell lung cancer. Cell Commun Signal. 2023;21(1):311. doi: 10.1186/s12964-023-01343-6
59. Gao Y, Ouyang X, Zuo L, Xiao Y, Sun Y, Chang C, et al. R-2HG downregulates ERα to inhibit cholangiocarcinoma via the FTO/m6A-methylated ERα/miR16-5p/YAP1 signal pathway. Mol Ther Oncolytics. 2021;23:65-81. doi: 10.1016/j.omto.2021.06.017
60. Gao Y, Yuan L, Ke C, Pei Z, Liu X, Wu R, et al. Caprin-1 plays a role in cell proliferation and Warburg metabolism of esophageal carcinoma by regulating METTL3 and WTAP. J Transl Med. 2023;21(1):159. doi: 10.1186/s12967-023-04001-0
61. Gill J, Gorlick R. Advancing therapy for osteosarcoma. Nat Rev Clin Oncol. 2021;18:609-24. doi: 10.1038/s41571-021-00519-8
62. Goh YT, Koh CWQ, Sim DY, Roca X, Goh WSS. METTL4 catalyzes m6Am methylation in U2 snRNA to regulate pre-mRNA splicing. Nucleic Acids Res. 2020;48:9250-61. doi: 10.1093/nar/gkaa684
63. Gong P-J, Shao Y-C, Yang Y, Song W-J, He X, Zeng Y-F, et al. Analysis of N6-methyladenosine methyltransferase reveals METTL14 and ZC3H13 as tumor suppressor genes in breast cancer. Front Oncol. 2020;10:578963. doi: 10.3389/fonc.2020.578963
64. Grabiec M, Sobstyl M, Skirecki T. Nod-like receptors: The relevant elements of glioblastoma`s prognostic puzzle. Pharmacol Res. 2024;208:107411. doi: 10.1016/j.phrs.2024.107411
65. Guo J-S, Ma J, Zhao X-H, Zhang J-F, Liu K-L, Li L-T, et al. DHPS-mediated hypusination regulates METTL3 Self-m6A-methylation modification to promote melanoma proliferation and the development of novel inhibitors. Adv Sci (Weinh). 2024;11(33):e2402450. doi: 10.1002/advs.202402450
66. Guo X, Li K, Jiang W, Hu Y, Xiao W, Huang Y, et al. RNA demethylase ALKBH5 prevents pancreatic cancer progression by posttranscriptional activation of PER1 in an m6A-YTHDF2-dependent manner. Mol Cancer. 2020;19(1):91. doi: 10.1186/s12943-020-01158-w
67. Guo Y-Q, Wang Q, Wang J-G, Gu Y-J, Song P-P, Wang S-Y, et al. METTL3 modulates m6A modification of CDC25B and promotes head and neck squamous cell carcinoma malignant progression. Exp Hematol Oncol. 2022;11(1):14. doi: 10.1186/s40164-022-00256-3
68. Han H, Li Z, Feng Y, Song H, Fang Z, Zhang D, et al. Peptide degrader-based targeting of METTL3/14 improves immunotherapy response in cutaneous melanoma. Angew Chem Int Ed Engl. 2024:e202407381. doi: 10.1002/anie.202407381
69. Han H, Yang C, Zhang S, Cheng M, Guo S, Zhu Y, et al. METTL3-mediated m6A mRNA modification promotes esophageal cancer initiation and progression via Notch signaling pathway. Mol Ther Nucleic Acids. 2021;26:333-46. doi: 10.1016/j.omtn.2021.07.007
70. Han J, Wang J-Z, Yang X, Yu H, Zhou R, Lu H-C, et al. METTL3 promote tumor proliferation of bladder cancer by accelerating pri-miR221/222 maturation in m6A-dependent manner. Mol Cancer. 2019;18(1):110. doi: 10.1186/s12943-019-1036-9
71. Han L, Dong L, Leung K, Zhao Z, Li Y, Gao L, et al. METTL16 drives leukemogenesis and leukemia stem cell self-renewal by reprogramming BCAA metabolism. Cell Stem Cell. 2023;30(1):52-68.e13. doi: 10.1016/j.stem.2022.12.006
72. Hao L, Wang J-M, Liu B-Q, Yan J, Li C, Jiang J-Y, et al. m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells. Biochim Biophys Acta Mol Cell Res. 2021;1868(1):118878. doi: 10.1016/j.bbamcr.2020.118878
73. Hao M, Li T, Xiao L, Liu Y. METTL3-induced FGD5-AS1 contributes to the tumorigenesis and PD-1/PD-L1 checkpoint to enhance the resistance to paclitaxel of endometrial carcinoma. J Cell Mol Med. 2024;28(5):e17971. doi: 10.1111/jcmm.17971
74. Hartmann AM, Nayler O, Schwaiger FW, Obermeier A, Stamm S. The interaction and colocalization of Sam68 with the splicing-associated factor YT521-B in nuclear dots is regulated by the Src family kinase p59(fyn). Mol Biol Cell. 1999;10(11):3909-26
75. He Y, Yue H, Cheng Y, Ding Z, Xu Z, Lv C, et al. ALKBH5-mediated m6A demethylation of KCNK15-AS1 inhibits pancreatic cancer progression via regulating KCNK15 and PTEN/AKT signaling. Cell Death Dis. 2021;12(12):1121. doi: 10.1038/s41419-021-04401-4
76. He Z, Zhong Y, Regmi P, Lv T, Ma W, Wang J, et al. Exosomal long non-coding RNA TRPM2-AS promotes angiogenesis in gallbladder cancer through interacting with PABPC1 to activate NOTCH1 signaling pathway. Mol Cancer. 2024;23(1):65. doi: 10.1186/s12943-024-01979-z
77. Hirschfeld M, Ouyang YQ, Jaeger M, Erbes T, Orlowska-Volk M, Zur Hausen A, et al. HNRNP G and HTRA2-BETA1 regulate estrogen receptor alpha expression with potential impact on endometrial cancer. BMC Cancer. 2015;15:86. doi: 10.1186/s12885-015-1088-1
78. Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019;18(1):163. doi: 10.1186/s12943-019-1082-3
79. Hou Y, Zhang Q, Pang W, Hou L, Liang Y, Han X, et al. YTHDC1-mediated augmentation of miR-30d in repressing pancreatic tumorigenesis via attenuation of RUNX1-induced transcriptional activation of Warburg effect. Cell Death Differ. 2021;28:3105-24. doi: 10.1038/s41418-021-00804-0
80. Hsu PJ, Shi H, Zhu AC, Lu Z, Miller N, Edens BM, et al. The RNA-binding protein FMRP facilitates the nuclear export of N6-methyladenosine-containing mRNAs. J Biol Chem. 2019;294:19889-95. doi: 10.1074/jbc.AC119.010078
81. Hsu PJ, Zhu Y, Ma H, Guo Y, Shi X, Liu Y, et al. Ythdc2 is an N6-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017;27:1115-27. doi: 10.1038/cr.2017.99
82. Hu Q, Yin J, Zhao S, Wang Y, Shi R, Yan K, et al. ZFHX3 acts as a tumor suppressor in prostate cancer by targeting FTO-mediated m6A demethylation. Cell Death Discov. 2024;10(1):284. doi: 10.1038/s41420-024-02060-w
83. Hu Y, Gong C, Li Z, Liu J, Chen Y, Huang Y, et al. Demethylase ALKBH5 suppresses invasion of gastric cancer via PKMYT1 m6A modification. Mol Cancer. 2022;21(1):34. doi: 10.1186/s12943-022-01522-y
84. Hu Y, Tang J, Xu F, Chen J, Zeng Z, Han S, et al. A reciprocal feedback between N6-methyladenosine reader YTHDF3 and lncRNA DICER1-AS1 promotes glycolysis of pancreatic cancer through inhibiting maturation of miR-5586-5p. J Exp Clin Cancer Res. 2022;41(1):69. doi: 10.1186/s13046-022-02285-6
85. Hua X, Xu Q, Wu R, Sun W, Gu Y, Zhu S, et al. ALKBH5 promotes non-small cell lung cancer progression and susceptibility to anti-PD-L1 therapy by modulating interactions between tumor and macrophages. J Exp Clin Cancer Res. 2024;43(1):164. doi: 10.1186/s13046-024-03073-0
86. Huang C, Xu R, Zhu X, Jiang H. m6A-modified circABCC4 promotes stemness and metastasis of prostate cancer by recruiting IGF2BP2 to increase stability of CCAR1. Cancer Gene Ther. 2023;30:1426-40. doi: 10.1038/s41417-023-00650-x
87. Huang C, Zhou S, Zhang C, Jin Y, Xu G, Zhou L, et al. ZC3H13-mediated N6-methyladenosine modification of PHF10 is impaired by fisetin which inhibits the DNA damage response in pancreatic cancer. Cancer Lett. 2022;530:16-28. doi: 10.1016/j.canlet.2022.01.013
88. Huang G-W, Chen Q-Q, Ma C-C, Xie L-H, Gu J. linc01305 promotes metastasis and proliferation of esophageal squamous cell carcinoma through interacting with IGF2BP2 and IGF2BP3 to stabilize HTR3A mRNA. Int J Biochem Cell Biol. 2021;136:106015. doi: 10.1016/j.biocel.2021.106015
89. Huang H, Li H, Pan R, Wang S, Khan AA, Zhao Y, et al. Ribosome 18S m6A methyltransferase METTL5 promotes pancreatic cancer progression by modulating c‑Myc translation. Int J Oncol. 2022;60(1):9. doi: 10.3892/ijo.2021.5299
90. Huang H, Wang Y, Kandpal M, Zhao G, Cardenas H, Ji Y, et al. FTO-Dependent N 6-methyladenosine modifications inhibit ovarian cancer stem cell self-renewal by blocking cAMP signaling. Cancer Res. 2020;80:3200-14. doi: 10.1158/0008-5472.CAN-19-4044
91. Huang H, Weng H, Sun W, Qin X, Shi H, Wu H, et al. Recognition of RNA N6-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20:285-95. doi: 10.1038/s41556-018-0045-z
92. Huang J, Sun W, Wang Z, Lv C, Zhang T, Zhang D, et al. FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner. J Exp Clin Cancer Res. 2022;41(1):42. doi: 10.1186/s13046-022-02254-z
93. Huang L, Liu X, Chen Q, Yang J, Zhang D, Zhao Y, et al. TGF-β-induced lncRNA TBUR1 promotes EMT and metastasis in lung adenocarcinoma via hnRNPC-mediated GRB2 mRNA stabilization. Cancer Lett. 2024;600:217153. doi: 10.1016/j.canlet.2024.217153
94. Huang X-T, Li J-H, Zhu X-X, Huang C-S, Gao Z-X, Xu Q-C, et al. HNRNPC impedes m6A-dependent anti-metastatic alternative splicing events in pancreatic ductal adenocarcinoma. Cancer Lett. 2021;518:196-206. doi: 10.1016/j.canlet.2021.07.016
95. Huang Y, Lv Y, Yang B, Zhang S, Bixia L, Zhang C, et al. Enhancing m6A modification of lncRNA through METTL3 and RBM15 to promote malignant progression in bladder cancer. Heliyon. 2024;10(7):e28165. doi: 10.1016/j.heliyon.2024.e28165
96. Huang Y, Su R, Sheng Y, Dong L, Dong Z, Xu H, et al. Small-molecule targeting of oncogenic FTO demethylase in acute myeloid leukemia. Cancer Cell. 2019;35(4):677-91.e10. doi: 10.1016/j.ccell.2019.03.006
97. Iaiza A, Tito C, Ianniello Z, Ganci F, Laquintana V, Gallo E, et al. METTL3-dependent MALAT1 delocalization drives c-Myc induction in thymic epithelial tumors. Clin Epigenetics. 2021;13(1):173. doi: 10.1186/s13148-021-01159-6
98. Ji F-H, Fu X-H, Li G-Q, He Q, Qiu X-G. FTO prevents thyroid cancer progression by SLC7A11 m6A methylation in a ferroptosis-dependent manner. Front Endocrinol (Lausanne). 2022;13:857765. doi: 10.3389/fendo.2022.857765
99. Ji Q, Guo Y, Li Z, Zhang X. WTAP regulates the production of reactive oxygen species, promotes malignant progression, and is closely related to the tumor microenvironment in glioblastoma. Aging (Albany NY). 2024;16:5601-17. doi: 10.18632/aging.205666
100. Ji X, Lv C, Huang J, Dong W, Sun W, Zhang H. ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2. Cancer Sci. 2023;114:2318-34. doi: 10.1111/cas.15772
101. Ji X, Wan X, Sun H, Deng Q, Meng S, Xie B, et al. METTL14 enhances the m6A modification level of lncRNA MSTRG.292666.16 to promote the progression of non-small cell lung cancer. Cancer Cell Int. 2024;24(1):61. doi: 10.1186/s12935-024-03250-3
102. Jia G, Fu Y, Zhao X, Dai Q, Zheng G, Yang Y, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7:885-7. doi: 10.1038/nchembio.687
103. Jia J, Yu L. METTL3-mediated m6A modification of EPPK1 to promote the development of esophageal cancer through regulating the PI3K/AKT pathway. Environ Toxicol. 2024;39:2830-41. doi: 10.1002/tox.24158
104. Jia Y, Yu X, Liu R, Shi L, Jin H, Yang D, et al. PRMT1 methylation of WTAP promotes multiple myeloma tumorigenesis by activating oxidative phosphorylation via m6A modification of NDUFS6. Cell Death Dis. 2023;14(8):512. doi: 10.1038/s41419-023-06036-z
105. Jiang L, Liang R, Luo Q, Chen Z, Song G. Targeting FTO suppresses hepatocellular carcinoma by inhibiting ERBB3 and TUBB4A expression. Biochem Pharmacol. 2024;226:116375. doi: 10.1016/j.bcp.2024.116375
106. Jiang L, Zhang Y, Qian J, Zhou X, Ma L, Zhu S, et al. The m6A methyltransferase METTL14 promotes cell proliferation via SETBP1-mediated activation of PI3K-AKT signaling pathway in myelodysplastic neoplasms. Leukemia. 2024;38:2246-58. doi: 10.1038/s41375-024-02350-3
107. Jiang M, Han J, Ma Q, Chen X, Xu R, Wang Q, et al. Nicotine-derived NNK promotes CRC progression through activating TMUB1/AKT pathway in METTL14/YTHDF2-mediated m6A manner. J Hazard Mater. 2024;467:133692. doi: 10.1016/j.jhazmat.2024.133692
108. Jiang T, Qi J, Xue Z, Liu B, Liu J, Hu Q, et al. The m6A modification mediated-lncRNA POU6F2-AS1 reprograms fatty acid metabolism and facilitates the growth of colorectal cancer via upregulation of FASN. Mol Cancer. 2024;23(1):55. doi: 10.1186/s12943-024-01962-8
109. Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6(1):74. doi: 10.1038/s41392-020-00450-x
110. Jiang Y, Zhang H, Li W, Yan Y, Yao X, Gu W. LINC01426 contributes to clear cell renal cell carcinoma progression by modulating CTBP1/miR-423-5p/FOXM1 axis via interacting with IGF2BP1. J Cell Physiol. 2021;236(1):427-39. doi: 10.1002/jcp.29871
111. Jin H, Chen Y, Zhang D, Lin J, Huang S, Wu X, et al. YTHDF2 favors protumoral macrophage polarization and implies poor survival outcomes in triple negative breast cancer. iScience. 2024;27(6):109902. doi: 10.1016/j.isci.2024.109902
112. Jin H, Ying X, Que B, Wang X, Chao Y, Zhang H, et al. N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer. EBioMedicine. 2019;47:195-207. doi: 10.1016/j.ebiom.2019.07.068
113. Jin T, Yang L, Chang C, Luo H, Wang R, Gan Y, et al. HnRNPA2B1 ISGylation regulates m6A-tagged mRNA selective export via ALYREF/NXF1 complex to foster breast cancer development. Adv Sci (Weinh). 2024;11(24):e2307639. doi: 10.1002/advs.202307639
114. Jin W, Yao Y, Fu Y, Lei X, Fu W, Lu Q, et al. WTAP/IGF2BP3-mediated GBE1 expression accelerates the proliferation and enhances stemness in pancreatic cancer cells via upregulating c-Myc. Cell Mol Biol Lett. 2024;29(1):97. doi: 10.1186/s11658-024-00611-8
115. Jin X, Liu L, Liu D, Wu J, Wang C, Wang S, et al. Unveiling the methionine cycle: a key metabolic signature and NR4A2 as a methionine-responsive oncogene in esophageal squamous cell carcinoma. Cell Death Differ. 2024;31:558-73. doi: 10.1038/s41418-024-01285-7
116. Lan T, Li H, Zhang D, Xu L, Liu H, Hao X, et al. KIAA1429 contributes to liver cancer progression through N6-methyladenosine-dependent post-transcriptional modification of GATA3. Mol Cancer. 2019;18(1):186. doi: 10.1186/s12943-019-1106-z
117. Lee H-H, Hsieh C-C, Chang C-C, Liao W-T, Chi H-C. YTHDF3 modulates EGFR/ATK/ERK/p21 signaling axis to promote cancer progression and osimertinib resistance of glioblastoma cells. Anticancer Res. 2023;43:5485-98. doi: 10.21873/anticanres.16751
118. Lee JH, Hong J, Zhang Z, de la Peña Avalos B, Proietti CJ, Deamicis AR, et al. Regulation of telomere homeostasis and genomic stability in cancer by N 6-adenosine methylation (m6A). Sci Adv. 2021;7(31):eabg7073. doi: 10.1126/sciadv.abg7073
119. Lee J-H, Wang R, Xiong F, Krakowiak J, Liao Z, Nguyen PT, et al. Enhancer RNA m6A methylation facilitates transcriptional condensate formation and gene activation. Mol Cell. 2021;81:3368-85.e9. doi: 10.1016/j.molcel.2021.07.024
120. Lesbirel S, Viphakone N, Parker M, Parker J, Heath C, Sudbery I, et al. The m6A-methylase complex recruits TREX and regulates mRNA export. Sci Rep. 2018;8 (1):13827. doi: 10.1038/s41598-018-32310-8
121. Lheureux S, Gourley C, Vergote I, Oza AM. Epithelial ovarian cancer. Lancet. 2019;393(10177):1240-53. doi: 10.1016/S0140-6736(18)32552-2
122. Li A, Cao C, Gan Y, Wang X, Wu T, Zhang Q, et al. ZNF677 suppresses renal cell carcinoma progression through N6-methyladenosine and transcriptional repression of CDKN3. Clin Transl Med. 2022;12(6):e906. doi: 10.1002/ctm2.906
123. Li B, Zhao R, Qiu W, Pan Z, Zhao S, Qi Y, et al. The N6-methyladenosine-mediated lncRNA WEE2-AS1 promotes glioblastoma progression by stabilizing RPN2. Theranostics. 2022;12:6363-79. doi: 10.7150/thno.74600
124. Li C, Liu J, Lyu Y, Ling S, Luo Y. METTL16 inhibits the malignant progression of epithelial ovarian cancer through the lncRNA MALAT1/β-catenin axis. Anal Cell Pathol (Amst). 2023;2023:9952234. doi: 10.1155/2023/9952234
125. Li F, Zhao J, Wang L, Chi Y, Huang X, Liu W. METTL14-mediated miR-30c-1-3p maturation represses the progression of lung cancer via regulation of MARCKSL1 expression. Mol Biotechnol. 2022;64:199-212. doi: 10.1007/s12033-021-00406-8
126. Li H, Cai L, Pan Q, Jiang X, Zhao J, Xiang T, et al. N6-methyladenosine-modified VGLL1 promotes ovarian cancer metastasis through high-mobility group AT-hook 1/Wnt/β-catenin signaling. iScience. 2024;27 (3):109245. doi: 10.1016/j.isci.2024.109245
127. Li H-B, Huang G, Tu J, Lv D-M, Jin Q-L, Chen J-K, et al. METTL14-mediated epitranscriptome modification of MN1 mRNA promote tumorigenicity and all-trans-retinoic acid resistance in osteosarcoma. EBioMedicine. 2022;82:104142. doi: 10.1016/j.ebiom.2022.104142
128. Li J, Xie H, Ying Y, Chen H, Yan H, He L, et al. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 2020;19(1):152. doi: 10.1186/s12943-020-01267-6
129. Li J, Xu X, Xu K, Zhou X, Wu K, Yao Y, et al. N6-methyladenosine-modified circSLCO1B3 promotes intrahepatic cholangiocarcinoma progression via regulating HOXC8 and PD-L1. J Exp Clin Cancer Res. 2024;43(1):119. doi: 10.1186/s13046-024-03006-x
130. Li K, Chen J, Lou X, Li Y, Qian B, Xu D, et al. HNRNPA2B1 affects the prognosis of esophageal cancer by regulating the miR-17-92 cluster. Front Cell Dev Biol. 2021;9:658642. doi: 10.3389/fcell.2021.658642
131. Li L, Zeng J, He S, Yang Y, Wang C. METTL14 decreases FTH1 mRNA stability via m6A methylation to promote sorafenib-induced ferroptosis of cervical cancer. Cancer Biol Ther. 2024;25(1):2349429. doi: 10.1080/15384047.2024.2349429
132. Li P, Shi Y, Gao D, Xu H, Zou Y, Wang Z, et al. ELK1-mediated YTHDF1 drives prostate cancer progression by facilitating the translation of Polo-like kinase 1 in an m6A dependent manner. Int J Biol Sci. 2022;18:6145-62. doi: 10.7150/ijbs.75063
133. Li Q, Wang C, Dong W, Su Y, Ma Z. WTAP facilitates progression of endometrial cancer via CAV-1/NF-κB axis. Cell Biol Int. 2021;45:1269-77. doi: 10.1002/cbin.11570
134. Li Q, Wang Y, Meng X, Wang W, Duan F, Chen S, et al. METTL16 inhibits papillary thyroid cancer tumorigenicity through m6A/YTHDC2/SCD1-regulated lipid metabolism. Cell Mol Life Sci. 2024;81(1):81. doi: 10.1007/s00018-024-05146-x
135. Li R, Song Y, Chen X, Chu M, Wang Z-W, Zhu X. METTL3 increases cisplatin chemosensitivity of cervical cancer cells via downregulation of the activity of RAGE. Mol Ther Oncolytics. 2021;22:245-55. doi: 10.1016/j.omto.2021.05.013
136. Li X, Yang G, Ma L, Tang B, Tao T. N6-methyladenosine (m6A) writer METTL5 represses the ferroptosis and antitumor immunity of gastric cancer. Cell Death Discov. 2024;10(1):402. doi: 10.1038/s41420-024-02166-1
137. Li Y, Guo X, Liang X, Wang Z. YTHDF1 promotes proliferation and inhibits apoptosis of gastric cancer cells via upregulating TCF7 mRNA translation. Front Biosci (Landmark Ed). 2024;29(3):117. doi: 10.31083/j.fbl2903117
138. Li Y, Luo B, Lin X, Bai D, Li L, Gao D, et al. 20(R)-panaxatriol enhances METTL3-mediated m6A modification of STUB1 to inhibit autophagy and exert antitumor effects in triple-negative breast cancer cells. Phytomedicine. 2024;130:155537. doi: 10.1016/j.phymed.2024.155537
139. Li Z, Weng H, Su R, Weng X, Zuo Z, Li C, et al. FTO plays an oncogenic role in acute myeloid leukemia as a N6-methyladenosine RNA demethylase. Cancer Cell. 2017;31(1):127-41. doi: 10.1016/j.ccell.2016.11.017
140. Lian B, Yan S, Li J, Bai Z, Li J. HNRNPC promotes collagen fiber alignment and immune evasion in breast cancer via activation of the VIRMA-mediated TFAP2A/DDR1 axis. Mol Med. 2023;29(1):103. doi: 10.1186/s10020-023-00696-5
141. Liang J, Cai H, Hou C, Song F, Jiang Y, Wang Z, et al. METTL14 inhibits malignant progression of oral squamous cell carcinoma by targeting the autophagy-related gene RB1CC1 in an m6A-IGF2BP2-dependent manner. Clin Sci (Lond). 2023;137:1373-89. doi: 10.1042/CS20230219
142. Liao Y, Liu Y, Yu C, Lei Q, Cheng J, Kong W, et al. HSP90β impedes STUB1-induced ubiquitination of YTHDF2 to drive sorafenib resistance in hepatocellular carcinoma. Adv Sci (Weinh). 2023;10(27):e2302025. doi: 10.1002/advs.202302025
143. Lin K, Zhou E, Shi T, Zhang S, Zhang J, Zheng Z, et al. m6A eraser FTO impairs gemcitabine resistance in pancreatic cancer through influencing NEDD4 mRNA stability by regulating the PTEN/PI3K/AKT pathway. J Exp Clin Cancer Res. 2023;42(1):217. doi: 10.1186/s13046-023-02792-0
144. Lin S, Zhu Y, Ji C, Yu W, Zhang C, Tan L, et al. METTL3-induced miR-222-3p upregulation inhibits STK4 and promotes the malignant behaviors of thyroid carcinoma cells. J Clin Endocrinol Metab. 2022;107:474-90. doi: 10.1210/clinem/dgab480
145. Lin X, Wang F, Chen J, Liu J, Lin Y-B, Li L, et al. N6-methyladenosine modification of CENPK mRNA by ZC3H13 promotes cervical cancer stemness and chemoresistance. Mil Med Res. 2022;9(1):19. doi: 10.1186/s40779-022-00378-z
146. Lin X, Ye R, Li Z, Zhang B, Huang Y, Du J, et al. KIAA1429 promotes tumorigenesis and gefitinib resistance in lung adenocarcinoma by activating the JNK/ MAPK pathway in an m6A-dependent manner. Drug Resist Updat. 2023;66:100908. doi: 10.1016/j.drup.2022.100908
147. Lin Z, Li J, Zhang J, Feng W, Lu J, Ma X, et al. Metabolic reprogramming driven by IGF2BP3 promotes acquired resistance to EGFR inhibitors in non-small cell lung cancer. Cancer Res. 2023;83:2187-207. doi: 10.1158/0008-5472.CAN-22-3059
148. Liu H, Li D, Sun L, Qin H, Fan A, Meng L, et al. Interaction of lncRNA MIR100HG with hnRNPA2B1 facilitates m6A-dependent stabilization of TCF7L2 mRNA and colorectal cancer progression. Mol Cancer. 2022;21(1):74. doi: 10.1186/s12943-022-01555-3
149. Liu H, Lyu H, Jiang G, Chen D, Ruan S, Liu S, et al. ALKBH5-mediated m6A demethylation of GLUT4 mRNA promotes glycolysis and resistance to HER2-targeted therapy in breast cancer. Cancer Res. 2022;82:3974-86. doi: 10.1158/0008-5472.CAN-22-0800
150. Liu J, Tian C, Qiao J, Deng K, Ye X, Xiong L. m6A methylation-mediated stabilization of LINC01106 suppresses bladder cancer progression by regulating the miR-3148/DAB1 axis. Biomedicines. 2024;12(1):114. doi: 10.3390/biomedicines12010114
151. Liu J, Yue Y, Han D, Wang X, Fu Y, Zhang L, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93-5. doi: 10.1038/nchembio.1432
152. Liu L, Gu M, Ma J, Wang Y, Li M, Wang H, et al. CircGPR137B/miR-4739/FTO feedback loop suppresses tumorigenesis and metastasis of hepatocellular carcinoma. Mol Cancer. 2022;21(1):149. doi: 10.1186/s12943-022-01619-4
153. Liu L, Wu Y, Li Q, Liang J, He Q, Zhao L, et al. METTL3 promotes tumorigenesis and metastasis through BMI1 m6A methylation in oral squamous cell carcinoma. Mol Ther. 2020;28:2177-90. doi: 10.1016/j.ymthe.2020.06.024
154. Liu N, Dai Q, Zheng G, He C, Parisien M, Pan T. N(6)-methyladenosine-dependent RNA structural switches regulate RNA-protein interactions. Nature. 2015;518 (7540):560-4. doi: 10.1038/nature14234
155. Liu N, Zhang J, Chen W, Ma W, Wu T. The RNA methyltransferase METTL16 enhances cholangiocarcinoma growth through PRDM15-mediated FGFR4 expression. J Exp Clin Cancer Res. 2023;42(1):263. doi: 10.1186/s13046-023-02844-5
156. Liu S, Lin C, Lin X, Lin P, He R, Pan X, et al. NAT10 phase separation regulates YTHDF1 splicing to promote gastric cancer progression. Cancer Res. 2024;84:3207-22. doi: 10.1158/0008-5472.CAN-23-4062
157. Liu T, Wei Q, Jin J, Luo Q, Liu Y, Yang Y, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48:3816-31. doi: 10.1093/nar/gkaa048
158. Liu T-Y, Hu C-C, Han C-Y, Mao S-Y, Zhang W-X, Xu Y-M, et al. IGF2BP2 promotes colorectal cancer progression by upregulating the expression of TFRC and enhancing iron metabolism. Biol Direct. 2023;18(1):19. doi: 10.1186/s13062-023-00373-x
159. Liu Y, Zhai E, Chen J, Qian Y, Zhao R, Ma Y, et al. m6 A-mediated regulation of PBX1-GCH1 axis promotes gastric cancer proliferation and metastasis by elevating tetrahydrobiopterin levels. Cancer Commun (Lond). 2022;42:327-44. doi: 10.1002/cac2.12281
160. Liu Y, Zhang N, Wen Y, Wen J. Head and neck cancer: pathogenesis and targeted therapy. MedComm (2020). 2024;5(9):e702. doi: 10.1002/mco2.702
161. Liu Z, Sun T, Piao C, Zhang Z, Kong C. METTL14-mediated N6-methyladenosine modification of ITGB4 mRNA inhibits metastasis of clear cell renal cell carcinoma. Cell Commun Signal. 2022;20(1):36. doi: 10.1186/s12964-022-00831-5
162. Liu Z, Wu K, Gu S, Wang W, Xie S, Lu T, et al. A methyltransferase-like 14/miR-99a-5p/tribble 2 positive feedback circuit promotes cancer stem cell persistence and radioresistance via histone deacetylase 2-mediated epigenetic modulation in esophageal squamous cell carcinoma. Clin Transl Med. 2021;11(9):e545. doi: 10.1002/ctm2.545
163. Luo J, Wang X, Chen Z, Zhou H, Xiao Y. The role and mechanism of JAK2/STAT3 signaling pathway regulated by m6A methyltransferase KIAA1429 in osteosarcoma. J Bone Oncol. 2023;39:100471. doi: 10.1016/j.jbo.2023.100471
164. Luo M, Luo X, Sun J, Ao X, Han H, Yang X. METTL5 enhances the mRNA stability of TPRKB through m6A modification to facilitate the aggressive phenotypes of hepatocellular carcinoma cell. Exp Cell Res. 2024;442 (1):114219. doi: 10.1016/j.yexcr.2024.114219
165. Luo Y, He M, Yang J, Zhang F, Chen J, Wen X, et al. A novel MYCN-YTHDF1 cascade contributes to retinoblastoma tumor growth by eliciting m6A -dependent activation of multiple oncogenes. Sci China Life Sci. 2023;66:2138-51. doi: 10.1007/s11427-022-2288-4
166. Lv D, Gimple RC, Zhong C, Wu Q, Yang K, Prager BC, et al. PDGF signaling inhibits mitophagy in glioblastoma stem cells through N6-methyladenosine. Dev Cell. 2022;57:1466-81.e6. doi: 10.1016/j.devcel.2022.05.007
167. Lv K, Xie P, Yang Q, Luo M, Li C. hsa_circ_0101050 regulated by ZC3H13 enhances tumorigenesis in papillary thyroid cancer via m6A modification. Heliyon. 2024;10(12):e32913. doi: 10.1016/j.heliyon.2024.e32913
168. Lv L, Wei Q, Zhang J, Dong Y, Shan Z, Chang N, et al. IGF2BP3 prevent HMGB1 mRNA decay in bladder cancer and development. Cell Mol Biol Lett. 2024;29 (1):39. doi: 10.1186/s11658-024-00545-1
169. Ma H, Wang X, Cai J, Dai Q, Natchiar SK, Lv R, et al. N6-Methyladenosine methyltransferase ZCCHC4 mediates ribosomal RNA methylation. Nat Chem Biol. 2019;15(1):88-94. doi: 10.1038/s41589-018-0184-3
170. Mao Z, Wang B, Zhang T, Cui B. The roles of m6A methylation in cervical cancer: functions, molecular mechanisms, and clinical applications. Cell Death Dis. 2023;14(11):734. doi: 10.1038/s41419-023-06265-2
171. Mendel M, Chen K-M, Homolka D, Gos P, Pandey RR, McCarthy AA, et al. Methylation of structured RNA by the m6A writer METTL16 is essential for mouse embryonic development. Mol Cell. 2018;71:986-1000.e11. doi: 10.1016/j.molcel.2018.08.004
172. Meyer KD, Saletore Y, Zumbo P, Elemento O, Mason CE, Jaffrey SR. Comprehensive analysis of mRNA methylation reveals enrichment in 3' UTRs and near stop codons. Cell. 2012;149:1635-46. doi: 10.1016/j.cell.2012.05.003
173. Miranda-Filho A, Piñeros M, Ferlay J, Soerjomataram I, Monnereau A, Bray F. Epidemiological patterns of leukaemia in 184 countries: a population-based study. Lancet Haematol. 2018;5(1):e14-24. doi: 10.1016/S2352-3026(17)30232-6
174. Miranda-Gonçalves V, Lobo J, Guimarães-Teixeira C, Barros-Silva D, Guimarães R, Cantante M, et al. The component of the m6A writer complex VIRMA is implicated in aggressive tumor phenotype, DNA damage response and cisplatin resistance in germ cell tumors. J Exp Clin Cancer Res. 2021;40(1):268. doi: 10.1186/s13046-021-02072-9
175. Montal R, Sia D, Montironi C, Leow WQ, Esteban-Fabró R, Pinyol R, et al. Molecular classification and therapeutic targets in extrahepatic cholangiocarcinoma. J Hepatol. 2020;73:315-27. doi: 10.1016/j.jhep.2020.03.008
176. Nayler O, Hartmann AM, Stamm S. The ER repeat protein YT521-B localizes to a novel subnuclear compartment. J Cell Biol. 2000;150:949-62
177. Ni J, Lu X, Gao X, Jin C, Mao J. Demethylase FTO inhibits the occurrence and development of triple-negative breast cancer by blocking m 6A-dependent miR-17-5p maturation-induced ZBTB4 depletion. Acta Biochim Biophys Sin (Shanghai). 2024;56(1):114-28. doi: 10.3724/abbs.2023267
178. Nie S, Zhang L, Liu J, Wan Y, Jiang Y, Yang J, et al. ALKBH5-HOXA10 loop-mediated JAK2 m6A demethylation and cisplatin resistance in epithelial ovarian cancer. J Exp Clin Cancer Res. 2021;40(1):284. doi: 10.1186/s13046-021-02088-1
179. Nielsen J, Christiansen J, Lykke-Andersen J, Johnsen AH, Wewer UM, Nielsen FC. A family of insulin-like growth factor II mRNA-binding proteins represses translation in late development. Mol Cell Biol. 1999;19:1262-70
180. Ning J, Hou X, Hao J, Zhang W, Shi Y, Huang Y, et al. METTL3 inhibition induced by M2 macrophage-derived extracellular vesicles drives anti-PD-1 therapy resistance via M6A-CD70-mediated immune suppression in thyroid cancer. Cell Death Differ. 2023;30:2265-79. doi: 10.1038/s41418-023-01217-x
181. Niu L, Li Y, Huang G, Huang W, Fu J, Feng L. FAM120A deficiency improves resistance to cisplatin in gastric cancer by promoting ferroptosis. Commun Biol. 2024;7(1):399. doi: 10.1038/s42003-024-06097-6
182. Ou B, Liu Y, Gao Z, Xu J, Yan Y, Li Y, et al. Senescent neutrophils-derived exosomal piRNA-17560 promotes chemoresistance and EMT of breast cancer via FTO-mediated m6A demethylation. Cell Death Dis. 2022;13(10):905. doi: 10.1038/s41419-022-05317-3
183. Ouyang L, Sun M-M, Zhou P-S, Ren Y-W, Liu X-Y, Wei W-Y, et al. LncRNA FOXD1-AS1 regulates pancreatic cancer stem cell properties and 5-FU resistance by regulating the miR-570-3p/SPP1 axis as a ceRNA. Cancer Cell Int. 2024;24(1):4. doi: 10.1186/s12935-023-03181-5
184. Ouyang P, Li K, Xu W, Chen C, Shi Y, Tian Y, et al. METTL3 recruiting M2-type immunosuppressed macrophages by targeting m6A-SNAIL-CXCL2 axis to promote colorectal cancer pulmonary metastasis. J Exp Clin Cancer Res. 2024;43(1):111. doi: 10.1186/s13046-024-03035-6
185. Pan X, Huang B, Ma Q, Ren J, Liu Y, Wang C, et al. Circular RNA circ-TNPO3 inhibits clear cell renal cell carcinoma metastasis by binding to IGF2BP2 and destabilizing SERPINH1 mRNA. Clin Transl Med. 2022;12(7):e994. doi: 10.1002/ctm2.994
186. Panebianco F, Kelly LM, Liu P, Zhong S, Dacic S, Wang X, et al. THADA fusion is a mechanism of IGF2BP3 activation and IGF1R signaling in thyroid cancer. Proc Natl Acad Sci U S A. 2017;114:2307-12. doi: 10.1073/pnas.1614265114
187. Park SH, Ju J-S, Woo H, Yun HJ, Lee SB, Kim S-H, et al. The m6A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolism. Exp Mol Med. 2024;56:1373-87. doi: 10.1038/s12276-024-01235-w
188. Patil DP, Chen C-K, Pickering BF, Chow A, Jackson C, Guttman M, et al. m(6)A RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537(7620):369-73. doi: 10.1038/nature19342
189. Pendleton KE, Chen B, Liu K, Hunter OV, Xie Y, Tu BP, et al. The U6 snRNA m6A methyltransferase METTL16 regulates SAM synthetase intron retention. Cell. 2017;169:824-35.e14. doi: 10.1016/j.cell.2017.05.003
190. Peng W-X, Liu F, Jiang J-H, Yuan H, Zhang Z, Yang L, et al. N6-methyladenosine modified LINC00901 promotes pancreatic cancer progression through IGF2BP2/MYC axis. Genes Dis. 2023;10:554-67. doi: 10.1016/j.gendis.2022.02.014
191. Ping X-L, Sun B-F, Wang L, Xiao W, Yang X, Wang W-J, et al. Mammalian WTAP is a regulatory subunit of the RNA N6-methyladenosine methyltransferase. Cell Res. 2014;24:177-89. doi: 10.1038/cr.2014.3
192. Piovani D, Nikolopoulos GK, Aghemo A, Lleo A, Alqahtani SA, Hassan C, et al. Environmental risk factors for gallbladder cancer: field-wide systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2024;epub ahead of print. doi: 10.1016/j.cgh.2024.07.046
193. Pu X, Gu Z, Gu Z. ALKBH5 regulates IGF1R expression to promote the proliferation and tumorigenicity of endometrial cancer. J Cancer. 2020;11:5612-22. doi: 10.7150/jca.46097
194. Qi F, Shen W, Wei X, Cheng Y, Xu F, Zheng Y, et al. CSNK1D-mediated phosphorylation of HNRNPA2B1 induces miR-25-3p/miR-93-5p maturation to promote prostate cancer cell proliferation and migration through m6A-dependent manner. Cell Mol Life Sci. 2023;80 (6):156. doi: 10.1007/s00018-023-04798-5
195. Qiao Y, Su M, Zhao H, Liu H, Wang C, Dai X, et al. Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression. J Exp Clin Cancer Res. 2024;43(1):108. doi: 10.1186/s13046-024-03032-9
196. Qiu D, Gao L, Yu X. Knockdown of YAP1 Reduces YTHDF3 to Stabilize SMAD7 and thus Inhibit Bladder Cancer Stem Cell Stemness. Discov Med. 2024;36:1486-98. doi: 10.24976/Discov.Med.202436186.138
197. Ren J, Huang B, Li W, Wang Y, Pan X, Ma Q, et al. RNA-binding protein IGF2BP2 suppresses metastasis of clear cell renal cell carcinoma by enhancing CKB mRNA stability and expression. Transl Oncol. 2024;42:101904. doi: 10.1016/j.tranon.2024.101904
198. Ren M, Pan H, Zhou X, Yu M, Ji F. KIAA1429 promotes gastric cancer progression by destabilizing RASD1 mRNA in an m6A-YTHDF2-dependent manner. J Transl Med. 2024;22(1):584. doi: 10.1186/s12967-024-05375-5
199. Ren W, Lu J, Huang M, Gao L, Li D, Wang GG, et al. Structure and regulation of ZCCHC4 in m6A-methylation of 28S rRNA. Nat Commun. 2019;10(1):5042. doi: 10.1038/s41467-019-12923-x
200. Ren W, Yuan Y, Li Y, Mutti L, Peng J, Jiang X. The function and clinical implication of YTHDF1 in the human system development and cancer. Biomark Res. 2023;11(1):5. doi: 10.1186/s40364-023-00452-1
201. Rong M, Zhang M, Dong F, Wu K, Cai B, Niu J, et al. LncRNA RASAL2-AS1 promotes METTL14-mediated m6A methylation in the proliferation and progression of head and neck squamous cell carcinoma. Cancer Cell Int. 2024;24(1):113. doi: 10.1186/s12935-024-03302-8
202. Rong Z-X, Li Z, He J-J, Liu L-Y, Ren X-X, Gao J, et al. Downregulation of fat mass and obesity associated (FTO) promotes the progression of intrahepatic cholangiocarcinoma. Front Oncol. 2019;9:369. doi: 10.3389/fonc.2019.00369
203. Roundtree IA, Evans ME, Pan T, He C. Dynamic RNA Modifications in gene expression regulation. Cell. 2017;169:1187-200. doi: 10.1016/j.cell.2017.05.045
204. Roundtree IA, Luo G-Z, Zhang Z, Wang X, Zhou T, Cui Y, et al. YTHDC1 mediates nuclear export of N6-methyladenosine methylated mRNAs. Elife. 2017;6:e31311. doi: 10.7554/eLife.31311
205. Sepich-Poore C, Zheng Z, Schmitt E, Wen K, Zhang ZS, Cui X-L, et al. The METTL5-TRMT112 N6-methyladenosine methyltransferase complex regulates mRNA translation via 18S rRNA methylation. J Biol Chem. 2022;298(3):101590. doi: 10.1016/j.jbc.2022.101590
206. Shen C, Sheng Y, Zhu AC, Robinson S, Jiang X, Dong L, et al. RNA demethylase ALKBH5 selectively promotes tumorigenesis and cancer stem cell self-renewal in acute myeloid leukemia. Cell Stem Cell. 2020;27(1):64-80.e9. doi: 10.1016/j.stem.2020.04.009
207. Shen D, Lin J, Xie Y, Zhuang Z, Xu G, Peng S, et al. RNA demethylase ALKBH5 promotes colorectal cancer progression by posttranscriptional activation of RAB5A in an m6A-YTHDF2-dependent manner. Clin Transl Med. 2023;13(5):e1279. doi: 10.1002/ctm2.1279
208. Shen H, Ying Y, Ma X, Xie H, Chen S, Sun J, et al. FTO promotes clear cell renal cell carcinoma progression via upregulation of PDK1 through an m6A dependent pathway. Cell Death Discov. 2022;8(1):356. doi: 10.1038/s41420-022-01151-w
209. Shen M, Li Y, Wang Y, Shao J, Zhang F, Yin G, et al. N6-methyladenosine modification regulates ferroptosis through autophagy signaling pathway in hepatic stellate cells. Redox Biol. 2021;47:102151. doi: 10.1016/j.redox.2021.102151
210. Shen X, Zhao K, Xu L, Cheng G, Zhu J, Gan L, et al. YTHDF2 inhibits gastric cancer cell growth by regulating FOXC2 signaling pathway. Front Genet. 2020;11:592042. doi: 10.3389/fgene.2020.592042
211. Shi H, Wang X, Lu Z, Zhao BS, Ma H, Hsu PJ, et al. YTHDF3 facilitates translation and decay of N6-methyladenosine-modified RNA. Cell Res. 2017;27:315-28. doi: 10.1038/cr.2017.15
212. Shi R, Zhao R, Shen Y, Wei S, Zhang T, Zhang J, et al. IGF2BP2-modified circular RNA circCHD7 promotes endometrial cancer progression via stabilizing PDGFRB and activating JAK/STAT signaling pathway. Cancer Gene Ther. 2024;31:1221-36. doi: 10.1038/s41417-024-00781-9-
213. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74(1):12-49. doi: 10.3322/caac.21820
214. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72(1):7-33. doi: 10.3322/caac.21708
215. Song P, Li X, Chen S, Gong Y, Zhao J, Jiao Y, et al. YTHDF1 mediates N-methyl-N-nitrosourea-induced gastric carcinogenesis by controlling HSPH1 translation. Cell Prolif. 2024;57(7):e13619. doi: 10.1111/cpr.13619
216. Song Y, Wu Q. RBM15 m6 A modification-mediated OTUB2 upregulation promotes cervical cancer progression via the AKT/mTOR signaling. Environ Toxicol. 2023;38:2155-64. doi: 10.1002/tox.23852
217. Stewart GD, Klatte T, Cosmai L, Bex A, Lamb BW, Moch H, et al. The multispeciality approach to the management of localised kidney cancer. Lancet. 2022;400(10351):523-34. doi: 10.1016/S0140-6736(22)01059-5
218. Strick A, von Hagen F, Gundert L, Klümper N, Tolkach Y, Schmidt D, et al. The N6 -methyladenosine (m6 A) erasers alkylation repair homologue 5 (ALKBH5) and fat mass and obesity-associated protein (FTO) are prognostic biomarkers in patients with clear cell renal carcinoma. BJU Int. 2020;125:617-24. doi: 10.1111/bju.15019
219. Su J, Li R, Chen Z, Liu S, Zhao H, Deng S, et al. N 6-methyladenosine modification of FZR1 mRNA promotes gemcitabine resistance in pancreatic cancer. Cancer Res. 2023;83:3059-76. doi: 10.1158/0008-5472.CAN-22-3346
220. Sun M, Wang L, Ge L, Xu D, Zhang R. IGF2BP1 facilitates non-small cell lung cancer progression by regulating the KIF2A-mediated Wnt/β-catenin pathway. Funct Integr Genomics. 2023;24(1):4. doi: 10.1007/s10142-023-01275-x
221. Sun M, Yue Y, Wang X, Feng H, Qin Y, Chen M, et al. ALKBH5-mediated upregulation of CPT1A promotes macrophage fatty acid metabolism and M2 macrophage polarization, facilitating malignant progression of colorectal cancer. Exp Cell Res. 2024;437(1):113994. doi: 10.1016/j.yexcr.2024.113994
222. Sun R, Yuan L, Jiang Y, Wan Y, Ma X, Yang J, et al. ALKBH5 activates FAK signaling through m6A demethylation in ITGB1 mRNA and enhances tumor-associated lymphangiogenesis and lymph node metastasis in ovarian cancer. Theranostics. 2023;13:833-48. doi: 10.7150/thno.77441
223. Sun S, Han Q, Liang M, Zhang Q, Zhang J, Cao J. Downregulation of m6 A reader YTHDC2 promotes tumor progression and predicts poor prognosis in non-small cell lung cancer. Thorac Cancer. 2020;11:3269-79. doi: 10.1111/1759-7714.13667
224. Sun T, Wu Z, Wang X, Wang Y, Hu X, Qin W, et al. LNC942 promoting METTL14-mediated m6A methylation in breast cancer cell proliferation and progression. Oncogene. 2020;39:5358-72. doi: 10.1038/s41388-020-1338-9
225. Sun Y, Chen D, Sun S, Ren M, Zhou L, Chen C, et al. RBMS1 coordinates with the m6A reader YTHDF1 to promote NSCLC metastasis through stimulating S100P translation. Adv Sci (Weinh). 2024;11(15):e2307122. doi: 10.1002/advs.202307122
226. Sun Y, Shen W, Hu S, Lyu Q, Wang Q, Wei T, et al. METTL3 promotes chemoresistance in small cell lung cancer by inducing mitophagy. J Exp Clin Cancer Res. 2023;42(1):65. doi: 10.1186/s13046-023-02638-9
227. Sun Z, Su Z, Zhou Z, Wang S, Wang Z, Tong X, et al. RNA demethylase ALKBH5 inhibits TGF-β-induced EMT by regulating TGF-β/SMAD signaling in non-small cell lung cancer. FASEB J. 2022;36(5):e22283. doi: 10.1096/fj.202200005RR
228. Suo D, Gao X, Chen Q, Zeng T, Zhan J, Li G, et al. HSPA4 upregulation induces immune evasion via ALKBH5/CD58 axis in gastric cancer. J Exp Clin Cancer Res. 2024;43(1):106. doi: 10.1186/s13046-024-03029-4
229. Tan B, Zhou K, Liu W, Prince E, Qing Y, Li Y, et al. RNA N6 -methyladenosine reader YTHDC1 is essential for TGF-beta-mediated metastasis of triple negative breast cancer. Theranostics. 2022;12:5727-43. doi: 10.7150/thno.71872
230. Tan J, Chen F, Wang J, Li J, Ouyang B, Li X, et al. ALKBH5 promotes the development of lung adenocarcinoma by regulating the polarization of M2 macrophages through CDCA4. Gene. 2024;895:147975. doi: 10.1016/j.gene.2023.147975
231. Tan M, He Y, Yi J, Chen J, Guo Q, Liao N, et al. WTAP mediates NUPR1 regulation of lcn2 through m6A modification to influence ferroptosis, thereby promoting breast cancer proliferation, migration and invasion. Biochem Genet. 2024;62:876-91. doi: 10.1007/s10528-023-10423-8
232. Tan M, Pan Q, Yu C, Zhai X, Gu J, Tao L, et al. PIGT promotes cell growth, glycolysis, and metastasis in bladder cancer by modulating GLUT1 glycosylation and membrane trafficking. J Transl Med. 2024;22 (1):5. doi: 10.1186/s12967-023-04805-0
233. Tan Z, Shi S, Xu J, Liu X, Lei Y, Zhang B, et al. RNA N6-methyladenosine demethylase FTO promotes pancreatic cancer progression by inducing the autocrine activity of PDGFC in an m6A-YTHDF2-dependent manner. Oncogene. 2022;41:2860-72. doi: 10.1038/s41388-022-02306-w
234. Tang B, Bi L, Xu Y, Cao L, Li X. N6-Methyladenosine (m6A) reader IGF2BP1 accelerates gastric cancer development and immune escape by targeting PD-L1. Mol Biotechnol. 2024;66:2850-59. doi: 10.1007/s12033-023-00896-8
235. Tassinari V, Cesarini V, Tomaselli S, Ianniello Z, Silvestris DA, Ginistrelli LC, et al. ADAR1 is a new target of METTL3 and plays a pro-oncogenic role in glioblastoma by an editing-independent mechanism. Genome Biol. 2021;22(1):51. doi: 10.1186/s13059-021-02271-9
236. Tavakoli S, Nabizadeh M, Makhamreh A, Gamper H, McCormick CA, Rezapour NK, et al. Semi-quantitative detection of pseudouridine modifications and type I/II hypermodifications in human mRNAs using direct long-read sequencing. Nat Commun. 2023;14(1):334. doi: 10.1038/s41467-023-35858-w
237. Tsuchiya K, Yoshimura K, Inoue Y, Iwashita Y, Yamada H, Kawase A, et al. YTHDF1 and YTHDF2 are associated with better patient survival and an inflamed tumor-immune microenvironment in non-small-cell lung cancer. Oncoimmunology. 2021;10(1):1962656. doi: 10.1080/2162402X.2021.1962656
238. Turkalj EM, Vissers C. The emerging importance of METTL5-mediated ribosomal RNA methylation. Exp Mol Med. 2022;54:1617-25. doi: 10.1038/s12276-022-00869-y
239. Vaid R, Thombare K, Mendez A, Burgos-Panadero R, Djos A, Jachimowicz D, et al. METTL3 drives telomere targeting of TERRA lncRNA through m6A-dependent R-loop formation: a therapeutic target for ALT-positive neuroblastoma. Nucleic Acids Res. 2024;52:2648-71. doi: 10.1093/nar/gkad1242
240. van Tran N, Ernst FGM, Hawley BR, Zorbas C, Ulryck N, Hackert P, et al. The human 18S rRNA m6A methyltransferase METTL5 is stabilized by TRMT112. Nucleic Acids Res. 2019;47:7719-33. doi: 10.1093/nar/gkz619
241. Wan B-S, Cheng M, Zhang L. Insulin-like growth factor 2 mRNA-binding protein 1 promotes cell proliferation via activation of AKT and is directly targeted by microRNA-494 in pancreatic cancer. World J Gastroenterol. 2019;25:6063-76. doi: 10.3748/wjg.v25.i40.6063
242. Wang A, Jin C, Wang Y, Yu J, Wang R, Tian X. FTO promotes the progression of cervical cancer by regulating the N6-methyladenosine modification of ZEB1 and Myc. Mol Carcinog. 2023;62:1228-37. doi: 10.1002/mc.23559
243. Wang B, Wang Y, Wang W, Wang Z, Zhang Y, Pan X, et al. WTAP/IGF2BP3 mediated m6A modification of the EGR1/PTEN axis regulates the malignant phenotypes of endometrial cancer stem cells. J Exp Clin Cancer Res. 2024;43(1):204. doi: 10.1186/s13046-024-03120-w
244. Wang C, Zhou M, Zhu P, Ju C, Sheng J, Du D, et al. IGF2BP2-induced circRUNX1 facilitates the growth and metastasis of esophageal squamous cell carcinoma through miR-449b-5p/FOXP3 axis. J Exp Clin Cancer Res. 2022;41(1):347. doi: 10.1186/s13046-022-02550-8
245. Wang H. The RNA m6A writer RBM15 contributes to the progression of esophageal squamous cell carcinoma by regulating miR-3605-5p/KRT4 pathway. Heliyon. 2024;10(2):e24459. doi: 10.1016/j.heliyon.2024.e24459
246. Wang H, Zhao S, Liu H, Liu Y, Zhang Z, Zhou Z, et al. ALKBH5 facilitates the progression of skin cutaneous melanoma via mediating ABCA1 demethylation and modulating autophagy in an m6A-dependent manner. Int J Biol Sci. 2024;20:1729-43. doi: 10.7150/ijbs.92994
247. Wang J, Fan P, Shen P, Fan C, Zhao P, Yao S, et al. XBP1s activates METTL3/METTL14 for ER-phagy and paclitaxel sensitivity regulation in breast cancer. Cancer Lett. 2024;596:216846. doi: 10.1016/j.canlet.2024.216846
248. Wang J, Li Y, Wang P, Han G, Zhang T, Chang J, et al. Leukemogenic chromatin alterations promote AML leukemia stem cells via a KDM4C-ALKBH5-AXL signaling axis. Cell Stem Cell. 2020;27(1):81-97.e8. doi: 10.1016/j.stem.2020.04.001
249. Wang J, Tan L, Jia B, Yu X, Yao R, Ouyang N, et al. Downregulation of m6A reader YTHDC2 promotes the proliferation and migration of malignant lung cells via CYLD/NF-κB pathway. Int J Biol Sci. 2021;17:2633-51. doi: 10.7150/ijbs.58514
250. Wang J, Tan L, Yu X, Cao X, Jia B, Chen R, et al. lncRNA ZNRD1-AS1 promotes malignant lung cell proliferation, migration, and angiogenesis via the miR-942/TNS1 axis and is positively regulated by the m6A reader YTHDC2. Mol Cancer. 2022;21(1):229. doi: 10.1186/s12943-022-01705-7
251. Wang J, Wang J, Gu Q, Ma Y, Yang Y, Zhu J, et al. The biological function of m6A demethylase ALKBH5 and its role in human disease. Cancer Cell Int. 2020;20:347. doi: 10.1186/s12935-020-01450-1
252. Wang J, Xiu M, Wang J, Gao Y, Li Y. METTL16-SENP3-LTF axis confers ferroptosis resistance and facilitates tumorigenesis in hepatocellular carcinoma. J Hematol Oncol. 2024;17(1):78. doi: 10.1186/s13045-024-01599-6
253. Wang J, Zhang J, Liu H, Meng L, Gao X, Zhao Y, et al. N6-methyladenosine reader hnRNPA2B1 recognizes and stabilizes NEAT1 to confer chemoresistance in gastric cancer. Cancer Commun (Lond). 2024;44:469-90. doi: 10.1002/cac2.12534
254. Wang J, Zheng F, Wang D, Yang Q. Regulation of ULK1 by WTAP/IGF2BP3 axis enhances mitophagy and progression in epithelial ovarian cancer. Cell Death Dis. 2024;15(1):97. doi: 10.1038/s41419-024-06477-0
255. Wang K, Shen K, Wang J, Yang K, Zhu J, Chen Y, et al. BUB1 potentiates gastric cancer proliferation and metastasis by activating TRAF6/NF-κB/FGF18 through m6A modification. Life Sci. 2024;353:122916. doi: 10.1016/j.lfs.2024.122916
256. Wang K, Wang G, Li G, Zhang W, Wang Y, Lin X, et al. m6A writer WTAP targets NRF2 to accelerate bladder cancer malignancy via m6A-dependent ferroptosis regulation. Apoptosis. 2023;28:627-38. doi: 10.1007/s10495-023-01817-5
257. Wang L, Peng J-L. METTL5 serves as a diagnostic and prognostic biomarker in hepatocellular carcinoma by influencing the immune microenvironment. Sci Rep. 2023;13(1):10755. doi: 10.1038/s41598-023-37807-5
258. Wang M, Liu J, Zhao Y, He R, Xu X, Guo X, et al. Upregulation of METTL14 mediates the elevation of PERP mRNA N6 adenosine methylation promoting the growth and metastasis of pancreatic cancer. Mol Cancer. 2020;19(1):130. doi: 10.1186/s12943-020-01249-8
259. Wang P, Doxtader KA, Nam Y. Structural basis for cooperative function of Mettl3 and Mettl14 methyltransferases. Mol Cell. 2016;63:306-17. doi: 10.1016/j.molcel.2016.05.041
260. Wang Q, Chen C, Xu X, Shu C, Cao C, Wang Z, et al. APAF1-Binding Long noncoding RNA promotes tumor growth and multidrug resistance in gastric cancer by blocking apoptosome assembly. Adv Sci (Weinh). 2022;9(28):e2201889. doi: 10.1002/advs.202201889
261. Wang Q, Huang Y, Jiang M, Tang Y, Wang Q, Bai L, et al. The demethylase ALKBH5 mediates ZKSCAN3 expression through the m6A modification to activate VEGFA transcription and thus participates in MNNG-induced gastric cancer progression. J Hazard Mater. 2024;473:134690. doi: 10.1016/j.jhazmat.2024.134690
262. Wang Q, Huang Y, Zhu Y, Zhang W, Wang B, Du X, et al. The m6A methyltransferase METTL5 promotes neutrophil extracellular trap network release to regulate hepatocellular carcinoma progression. Cancer Med. 2024;13(7):e7165. doi: 10.1002/cam4.7165
263. Wang R, Gao X, Xie L, Lin J, Ren Y. METTL16 regulates the mRNA stability of FBXO5 via m6A modification to facilitate the malignant behavior of breast cancer. Cancer Metab. 2024;12(1):22. doi: 10.1186/s40170-024-00351-5
264. Wang R, Ye H, Yang B, Ao M, Yu X, Wu Y, et al. m6A-modified circNFIX promotes ovarian cancer progression and immune escape via activating IL-6R/JAK1/STAT3 signaling by sponging miR-647. Int Immunopharmacol. 2023;124(Pt A):110879. doi: 10.1016/j.intimp.2023.110879
265. Wang R-j, Li J-w, Bao B-h, Wu H-c, Du Z-h, Su J-l, et al. MicroRNA-873 (miRNA-873) inhibits glioblastoma tumorigenesis and metastasis by suppressing the expression of IGF2BP1. J Biol Chem. 2015;290:8938-48. doi: 10.1074/jbc.M114.624700
266. Wang S, Lv W, Li T, Zhang S, Wang H, Li X, et al. Dynamic regulation and functions of mRNA m6A modification. Cancer Cell Int. 2022;22(1):48. doi: 10.1186/s12935-022-02452-x
267. Wang S, Xu L, Wang D, Zhao S, Li K, Ma F, et al. YTHDF1 promotes the osteolytic bone metastasis of breast cancer via inducing EZH2 and CDH11 translation. Cancer Lett. 2024;597:217047. doi: 10.1016/j.canlet.2024.217047
268. Wang W, Ding Y, Zhao Y, Li X. m6A reader IGF2BP2 promotes lymphatic metastasis by stabilizing DPP4 in papillary thyroid carcinoma. Cancer Gene Ther. 2024;31:285-99. doi: 10.1038/s41417-023-00702-2
269. Wang W, He Y, Wu L, Zhai L-L, Chen L-J, Yao L-C, et al. N6 -methyladenosine RNA demethylase FTO regulates extracellular matrix-related genes and promotes pancreatic cancer cell migration and invasion. Cancer Med. 2023;12:3731-43. doi: 10.1002/cam4.5054
270. Wang W, He Y, Yao L-C, Yuan Y, Lu C, Xiong L-K, et al. Identification of m6A modification patterns and RBM15 mediated macrophage phagocytosis in pancreatic cancer: An integrative analysis. Biochim Biophys Acta Mol Basis Dis. 2024;1870(7):167304. doi: 10.1016/j.bbadis.2024.167304
271. Wang W, Huang Q, Liao Z, Zhang H, Liu Y, Liu F, et al. ALKBH5 prevents hepatocellular carcinoma progression by post-transcriptional inhibition of PAQR4 in an m6A dependent manner. Exp Hematol Oncol. 2023;12(1):1. doi: 10.1186/s40164-022-00370-2
272. Wang X, Chen Q, Bing Z, Zhou S, Xu Z, Hou Y, et al. Low expression of m6A reader YTHDC1 promotes progression of ovarian cancer via PIK3R1/STAT3/ GANAB axis. Int J Biol Sci. 2023;19:4672-88. doi: 10.7150/ijbs.81595
273. Wang X, Liu Y, Zhou M, Yu L, Si Z. m6A modified BACE1-AS contributes to liver metastasis and stemness-like properties in colorectal cancer through TUFT1 dependent activation of Wnt signaling. J Exp Clin Cancer Res. 2023;42(1):306. doi: 10.1186/s13046-023-02881-0
274. Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505(7481):117-20. doi: 10.1038/nature12730
275. Wang X, Tian L, Li Y, Wang J, Yan B, Yang L, et al. RBM15 facilitates laryngeal squamous cell carcinoma progression by regulating TMBIM6 stability through IGF2BP3 dependent. J Exp Clin Cancer Res. 2021;40(1):80. doi: 10.1186/s13046-021-01871-4
276. Wang X, Zhao BS, Roundtree IA, Lu Z, Han D, Ma H, et al. N(6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161:1388-99. doi: 10.1016/j.cell.2015.05.014
277. Wang Y, Jin P, Wang X. N6-methyladenosine regulator YTHDF1 represses the CD8???+???T cell-mediated antitumor immunity and ferroptosis in prostate cancer via m6A/PD-L1 manner. Apoptosis. 2024;29(1-2):142-53. doi: 10.1007/s10495-023-01885-7
278. Wang Y, Wang C, Guan X, Ma Y, Zhang S, Li F, et al. PRMT3-mediated arginine methylation of METTL14 promotes malignant progression and treatment resistance in endometrial carcinoma. Adv Sci (Weinh). 2023;10(36):e2303812. doi: 10.1002/advs.202303812
279. Wang Y-Y, Ye L-H, Zhao A-Q, Gao W-R, Dai N, Yin Y, et al. M6A modification regulates tumor suppressor DIRAS1 expression in cervical cancer cells. Cancer Biol Ther. 2024;25(1):2306674. doi: 10.1080/15384047.2024.2306674
280. Warda AS, Kretschmer J, Hackert P, Lenz C, Urlaub H, Höbartner C, et al. Human METTL16 is a N6-methyladenosine (m6A) methyltransferase that targets pre-mRNAs and various non-coding RNAs. EMBO Rep. 2017;18:2004-14. doi: 10.15252/embr.201744940
281. Wei C, Peng D, Jing B, Wang B, Li Z, Yu R, et al. A novel protein SPECC1-415aa encoded by N6-methyladenosine modified circSPECC1 regulates the sensitivity of glioblastoma to TMZ. Cell Mol Biol Lett. 2024;29(1):127. doi: 10.1186/s11658-024-00644-z
282. Wei J, Liu F, Lu Z, Fei Q, Ai Y, He PC, et al. Differential m6A, m6Am, and m1A demethylation mediated by FTO in the cell nucleus and cytoplasm. Mol Cell. 2018;71:973-85.e5. doi: 10.1016/j.molcel.2018.08.011
283. Wei W, Sun J, Zhang H, Xiao X, Huang C, Wang L, et al. Circ0008399 interaction with WTAP promotes assembly and activity of the m6A methyltransferase complex and promotes cisplatin resistance in bladder cancer. Cancer Res. 2021;81:6142-56. doi: 10.1158/0008-5472.CAN-21-1518
284. Wei X, Feng J, Chen L, Zhang C, Liu Y, Zhang Y, et al. METTL3-mediated m6A modification of LINC00520 confers glycolysis and chemoresistance in osteosarcoma via suppressing ubiquitination of ENO1. Cancer Lett. 2024:217194;epub ahead of print. doi: 10.1016/j.canlet.2024.217194
285. Wen D, Xiao H, Gao Y, Zeng H, Deng J. N6-methyladenosine-modified SENP1, identified by IGF2BP3, is a novel molecular marker in acute myeloid leukemia and aggravates progression by activating AKT signal via de-SUMOylating HDAC2. Mol Cancer. 2024;23 (1):116. doi: 10.1186/s12943-024-02013-y
286. Wen J, Lv R, Ma H, Shen H, He C, Wang J, et al. Zc3h13 regulates nuclear RNA m6A methylation and mouse embryonic stem cell self-renewal. Mol Cell. 2018;69:1028-36.e6. doi: 10.1016/j.molcel.2018.02.015
287. Wen J, Xue L, Wei Y, Liang J, Jia W, Yong T, et al. YTHDF2 Is a therapeutic target for HCC by suppressing immune evasion and angiogenesis through ETV5/PD-L1/VEGFA axis. Adv Sci (Weinh). 2024;11 (13):e2307242. doi: 10.1002/advs.202307242
288. Woodcock CL, Alsaleem M, Toss MS, Lothion-Roy J, Harris AE, Jeyapalan JN, et al. The role of the ALKBH5 RNA demethylase in invasive breast cancer. Discov Oncol. 2024;15(1):343. doi: 10.1007/s12672-024-01205-8
289. Wu G, Hou Q, Liu Z, Pu Z, Wu L. N6-methyladenosine-modified circ_0006168 promotes epithelial mesenchymal transition via miR-384/STAT3/Snail axis in esophageal squamous cell carcinoma. J Cancer. 2024;15:4939-54. doi: 10.7150/jca.97533
290. Wu N, Sun Y, Xue D, He X. FTO promotes the progression of bladder cancer via demethylating m6A modifications in PTPN6 mRNA. Heliyon. 2024;10 (14):e34031. doi: 10.1016/j.heliyon.2024.e34031
291. Wu Q, Zhang H, Yang D, Min Q, Wang Y, Zhang W, et al. The m6A-induced lncRNA CASC8 promotes proliferation and chemoresistance via upregulation of hnRNPL in esophageal squamous cell carcinoma. Int J Biol Sci. 2022;18:4824-36. doi: 10.7150/ijbs.71234
292. Wu R, Li A, Sun B, Sun J-G, Zhang J, Zhang T, et al. A novel m6A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res. 2019;29(1):23-41. doi: 10.1038/s41422-018-0113-8
293. Wu S, He G, Liu S, Cao Y, Geng C, Pan H. Identification and validation of the N6-methyladenosine RNA methylation regulator ZC3H13 as a novel prognostic marker and potential target for hepatocellular carcinoma. Int J Med Sci. 2022;19:618-30. doi: 10.7150/ijms.69645
294. Wu X, Chen H, Li K, Zhang H, Li K, Tan H. The biological function of the N6-Methyladenosine reader YTHDC2 and its role in diseases. J Transl Med. 2024;22(1):490. doi: 10.1186/s12967-024-05293-6
295. Wu X, Fang Y, Gu Y, Shen H, Xu Y, Xu T, et al. Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay. Mol Biomed. 2024;5(1):11. doi: 10.1186/s43556-024-00172-4
296. Wu Y, Li H, Huang Y, Chen Q. Silencing of m6A methyltransferase KIAA1429 suppresses the progression of non-small cell lung cancer by promoting the p53 signaling pathway and ferroptosis. Am J Cancer Res. 2023;13:5320-33
297. Xi Q, Yang G, He X, Zhuang H, Li L, Lin B, et al. M6A-mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages. Adv Sci (Weinh). 2024:e2400695. doi: 10.1002/advs.202400695
298. Xia P, Zhang H, Lu H, Xu K, Jiang X, Jiang Y, et al. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Cancer Commun (Lond). 2023;43:338-64. doi: 10.1002/cac2.12403
299. Xia T, Dai X-Y, Sang M-Y, Zhang X, Xu F, Wu J, et al. IGF2BP2 drives cell cycle progression in triple-negative breast cancer by recruiting EIF4A1 to promote the m6A-modified CDK6 translation initiation process. Adv Sci (Weinh). 2024;11(1):e2305142. doi: 10.1002/advs.202305142
300. Xiao W, Adhikari S, Dahal U, Chen Y-S, Hao Y-J, Sun B-F, et al. Nuclear m(6)A reader YTHDC1 regulates mRNA splicing. Mol Cell. 2016;61:507-19. doi: 10.1016/j.molcel.2016.01.012
301. Xie F, Huang C, Liu F, Zhang H, Xiao X, Sun J, et al. CircPTPRA blocks the recognition of RNA N6-methyladenosine through interacting with IGF2BP1 to suppress bladder cancer progression. Mol Cancer. 2021;20(1):68. doi: 10.1186/s12943-021-01359-x
302. Xie X, Lin J, Fan X, Zhong Y, Chen Y, Liu K, et al. LncRNA CDKN2B-AS1 stabilized by IGF2BP3 drives the malignancy of renal clear cell carcinoma through epigenetically activating NUF2 transcription. Cell Death Dis. 2021;12(2):201. doi: 10.1038/s41419-021-03489-y
303. Xu F, Li J, Ni M, Cheng J, Zhao H, Wang S, et al. FBW7 suppresses ovarian cancer development by targeting the N6-methyladenosine binding protein YTHDF2. Mol Cancer. 2021;20(1):45. doi: 10.1186/s12943-021-01340-8
304. Xu W, Huang Z, Xiao Y, Li W, Xu M, Zhao Q, et al. HNRNPC promotes estrogen receptor-positive breast cancer cell cycle by stabilizing WDR77 mRNA in an m6A-dependent manner. Mol Carcinog. 2024;63:859-73. doi: 10.1002/mc.23693
305. Xu W, Lai Y, Pan Y, Tan M, Ma Y, Sheng H, et al. m6A RNA methylation-mediated NDUFA4 promotes cell proliferation and metabolism in gastric cancer. Cell Death Dis. 2022;13(8):715. doi: 10.1038/s41419-022-05132-w
306. Xu W, Liu S, Zhang G, Liu J, Cao G. Knockdown of METTL5 inhibits the Myc pathway to downregulate PD-L1 expression and inhibits immune escape of hepatocellular carcinoma cells. J Chemother. 2023;35:455-64. doi: 10.1080/1120009X.2022.2143614
307. Xu X, Zhuang X, Yu H, Li P, Li X, Lin H, et al. FSH induces EMT in ovarian cancer via ALKBH5-regulated Snail m6A demethylation. Theranostics. 2024;14:2151-66. doi: 10.7150/thno.94161
308. Xu Y, Song M, Hong Z, Chen W, Zhang Q, Zhou J, et al. The N6-methyladenosine METTL3 regulates tumorigenesis and glycolysis by mediating m6A methylation of the tumor suppressor LATS1 in breast cancer. J Exp Clin Cancer Res. 2023;42(1):10. doi: 10.1186/s13046-022-02581-1
309. Xu Y, Ye S, Zhang N, Zheng S, Liu H, Zhou K, et al. The FTO/miR-181b-3p/ARL5B signaling pathway regulates cell migration and invasion in breast cancer. Cancer Commun (Lond). 2020;40:484-500. doi: 10.1002/cac2.12075
310. Xu Y, Zhou J, Li L, Yang W, Zhang Z, Zhang K, et al. FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability. Int J Biol Sci. 2022;18:5943-62. doi: 10.7150/ijbs.77774
311. Yan B, Li X, Peng M, Zuo Y, Wang Y, Liu P, et al. The YTHDC1/GLUT3/RNF183 axis forms a positive feedback loop that modulates glucose metabolism and bladder cancer progression. Exp Mol Med. 2023;55:1145-58. doi: 10.1038/s12276-023-00997-z
312. Yan Y, Ma J, Chen Q, Zhang T, Fan R, Du J. GAS5 regulated by FTO-mediated m6A modification suppresses cell proliferation via the IGF2BP2/QKI axis in breast cancer. Discov Oncol. 2024;15(1):182. doi: 10.1007/s12672-024-01051-8
313. Yang F, Liu Y, Xiao J, Li B, Chen Y, Hu A, et al. Circ-CTNNB1 drives aerobic glycolysis and osteosarcoma progression via m6A modification through interacting with RBM15. Cell Prolif. 2023;56(1):e13344. doi: 10.1111/cpr.13344
314. Yang H, Hu Y, Weng M, Liu X, Wan P, Hu Y, et al. Hypoxia inducible lncRNA-CBSLR modulates ferroptosis through m6A-YTHDF2-dependent modulation of CBS in gastric cancer. J Adv Res. 2022;37:91-106. doi: 10.1016/j.jare.2021.10.001
315. Yang L, Yan B, Qu L, Ren J, Li Q, Wang J, et al. IGF2BP3 Regulates TMA7-mediated Autophagy and Cisplatin Resistance in Laryngeal Cancer via m6A RNA Methylation. Int J Biol Sci. 2023;19:1382-400. doi: 10.7150/ijbs.80921
316. Yang X, Zhang S, He C, Xue P, Zhang L, He Z, et al. METTL14 suppresses proliferation and metastasis of colorectal cancer by down-regulating oncogenic long non-coding RNA XIST. Mol Cancer. 2020;19(1):46. doi: 10.1186/s12943-020-1146-4
317. Yang Y, Cheng C, He B, Du X, Liu J, Xia H, et al. Cigarette smoking, by accelerating the cell cycle, promotes the progression of non-small cell lung cancer through an HIF-1α-METTL3-m6A/CDK2AP2 axis. J Hazard Mater. 2023;455:131556. doi: 10.1016/j.jhazmat.2023.131556
318. Yang Y, Hsu PJ, Chen Y-S, Yang Y-G. Dynamic transcriptomic m6A decoration: writers, erasers, readers and functions in RNA metabolism. Cell Res. 2018;28:616-24. doi: 10.1038/s41422-018-0040-8
319. Yang Y, Yan Y, Yin J, Tang N, Wang K, Huang L, et al. O-GlcNAcylation of YTHDF2 promotes HBV-related hepatocellular carcinoma progression in an N6-methyladenosine-dependent manner. Signal Transduct Target Ther. 2023;8(1):63. doi: 10.1038/s41392-023-01316-8
320. Yankova E, Blackaby W, Albertella M, Rak J, De Braekeleer E, Tsagkogeorga G, et al. Small-molecule inhibition of METTL3 as a strategy against myeloid leukaemia. Nature. 2021;593(7860):597-601. doi: 10.1038/s41586-021-03536-w
321. Yarmishyn AA, Yang Y-P, Lu K-H, Chen Y-C, Chien Y, Chou S-J, et al. Musashi-1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1. Cancer Cell Int. 2020;20(1):597. doi: 10.1186/s12935-020-01696-9
322. Ye M, Chen J, Lu F, Zhao M, Wu S, Hu C, et al. Down-regulated FTO and ALKBH5 co-operatively activates FOXO signaling through m6A methylation modification in HK2 mRNA mediated by IGF2BP2 to enhance glycolysis in colorectal cancer. Cell Biosci. 2023;13 (1):148. doi: 10.1186/s13578-023-01100-9
323. Ying Y, Wu Y, Zhang F, Tang Y, Yi J, Ma X, et al. Co-transcriptional R-loops-mediated epigenetic regulation drives growth retardation and docetaxel chemosensitivity enhancement in advanced prostate cancer. Mol Cancer. 2024;23(1):79. doi: 10.1186/s12943-024-01994-0
324. Yu H, Zhuang J, Zhou Z, Song Q, Lv J, Yang X, et al. METTL16 suppressed the proliferation and cisplatin-chemoresistance of bladder cancer by degrading PMEPA1 mRNA in a m6A manner through autophagy pathway. Int J Biol Sci. 2024;20:1471-91. doi: 10.7150/ijbs.86719
325. Yu Y, Yang Y-L, Chen X-Y, Chen Z-Y, Zhu J-S, Zhang J. Helicobacter pylori-enhanced hnRNPA2B1 coordinates with PABPC1 to promote non-m6A translation and gastric cancer progression. Adv Sci (Weinh). 2024;11(30):e2309712. doi: 10.1002/advs.202309712
326. Yuan J, Guan W, Li X, Wang F, Liu H, Xu G. RBM15‑mediating MDR1 mRNA m6A methylation regulated by the TGF‑β signaling pathway in paclitaxel‑resistant ovarian cancer. Int J Oncol. 2023;63(4):112. doi: 10.3892/ijo.2023.5560
327. Yuan S, Xi S, Weng H, Guo M-M, Zhang J-H, Yu Z-P, et al. YTHDC1 as a tumor progression suppressor through modulating FSP1-dependent ferroptosis suppression in lung cancer. Cell Death Differ. 2023;30:2477-90. doi: 10.1038/s41418-023-01234-w
328. Yuan W, Chen S, Li B, Han X, Meng B, Zou Y, et al. The N6-methyladenosine reader protein YTHDC2 promotes gastric cancer progression via enhancing YAP mRNA translation. Transl Oncol. 2022;16:101308. doi: 10.1016/j.tranon.2021.101308
329. Yue Y, Liu J, Cui X, Cao J, Luo G, Zhang Z, et al. VIRMA mediates preferential m6A mRNA methylation in 3'UTR and near stop codon and associates with alternative polyadenylation. Cell Discov. 2018;4:10. doi: 10.1038/s41421-018-0019-0
330. Zeng X, Chen K, Li L, Tian J, Ruan W, Hu Z, et al. Epigenetic activation of RBM15 promotes clear cell renal cell carcinoma growth, metastasis and macrophage infiltration by regulating the m6A modification of CXCL11. Free Radic Biol Med. 2022;184:135-47. doi: 10.1016/j.freeradbiomed.2022.03.031
331. Zeng X, Lu Y, Zeng T, Liu W, Huang W, Yu T, et al. RNA demethylase FTO participates in malignant progression of gastric cancer by regulating SP1-AURKB-ATM pathway. Commun Biol. 2024;7(1):800. doi: 10.1038/s42003-024-06477-y
332. Zeng Y, Luo Y, Zhao K, Liu S, Wu K, Wu Y, et al. m6A-mediated induction of 7-dehydrocholesterol reductase stimulates cholesterol synthesis and camp signaling to promote bladder cancer metastasis. Cancer Res. 2024;84:3402-18. doi: 10.1158/0008-5472.CAN-23-3703
333. Zhai J, Chen H, Wong CC, Peng Y, Gou H, Zhang J, et al. ALKBH5 drives immune suppression via targeting AXIN2 to promote colorectal cancer and is a target for boosting immunotherapy. Gastroenterology. 2023;165:445-62. doi: 10.1053/j.gastro.2023.04.032
334. Zhan L, Zhang J, Zhang J-H, Liu X-J, Guo B, Chen J-H, et al. METTL3 facilitates immunosurveillance by inhibiting YTHDF2-mediated NLRC5 mRNA degradation in endometrial cancer. Biomark Res. 2023;11(1):43. doi: 10.1186/s40364-023-00479-4
335. Zhang B, Qian R, Li X. METTL3 suppresses invasion of lung cancer via SH3BP5 m6A modification. Arch Biochem Biophys. 2024;752:109876. doi: 10.1016/j.abb.2023.109876
336. Zhang C, Chen L, Lou W, Su J, Huang J, Liu A, et al. Aberrant activation of m6A demethylase FTO renders HIF2αlow/- clear cell renal cell carcinoma sensitive to BRD9 inhibitors. Sci Transl Med. 2021;13(613):eabf6045. doi: 10.1126/scitranslmed.abf6045
337. Zhang C, Chen L, Xie C, Wang F, Wang J, Zhou H, et al. YTHDC1 delays cellular senescence and pulmonary fibrosis by activating ATR in an m6A-independent manner. EMBO J. 2024;43(1):61-86. doi: 10.1038/s44318-023-00003-2
338. Zhang C, Sun Q, Zhang X, Qin N, Pu Z, Gu Y, et al. Gene amplification-driven RNA methyltransferase KIAA1429 promotes tumorigenesis by regulating BTG2 via m6A-YTHDF2-dependent in lung adenocarcinoma. Cancer Commun (Lond). 2022;42:609-26. doi: 10.1002/cac2.12325
339. Zhang F, Kang Y, Wang M, Li Y, Xu T, Yang W, et al. Fragile X mental retardation protein modulates the stability of its m6A-marked messenger RNA targets. Hum Mol Genet. 2018;27:3936-50. doi: 10.1093/hmg/ddy292
340. Zhang H, Sun Y, Wang Z, Huang X, Tang L, Jiang K, et al. ZDHHC20-mediated S-palmitoylation of YTHDF3 stabilizes MYC mRNA to promote pancreatic cancer progression. Nat Commun. 2024;15(1):4642. doi: 10.1038/s41467-024-49105-3
341. Zhang J, Bai R, Li M, Ye H, Wu C, Wang C, et al. Excessive miR-25-3p maturation via N6-methyladenosine stimulated by cigarette smoke promotes pancreatic cancer progression. Nat Commun. 2019;10(1):1858. doi: 10.1038/s41467-019-09712-x
342. Zhang L, Cai E, Xu Y, Liu Z, Zheng M, Sun Z, et al. YTHDF1 facilitates esophageal cancer progression via augmenting m6A-dependent TINAGL1 translation. Cell Signal. 2024;122:111332. doi: 10.1016/j.cellsig.2024.111332
343. Zhang L, Li Y, Zhou L, Zhou H, Ye L, Ou T, et al. The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response. Cancer Res. 2023;83:1834-50. doi: 10.1158/0008-5472.CAN-22-2485
344. Zhang L, Wan Y, Zhang Z, Jiang Y, Gu Z, Ma X, et al. IGF2BP1 overexpression stabilizes PEG10 mRNA in an m6A-dependent manner and promotes endometrial cancer progression. Theranostics. 2021;11:1100-14. doi: 10.7150/thno.49345
345. Zhang L, Wan Y, Zhang Z, Jiang Y, Lang J, Cheng W, et al. FTO demethylates m6A modifications in HOXB13 mRNA and promotes endometrial cancer metastasis by activating the WNT signalling pathway. RNA Biol. 2021;18:1265-78. doi: 10.1080/15476286.2020.1841458
346. Zhang Q, Zhang J, Ye J, Li X, Liu H, Ma X, et al. Nuclear speckle specific hnRNP D-like prevents age- and AD-related cognitive decline by modulating RNA splicing. Mol Neurodegener. 2021;16(1):66. doi: 10.1186/s13024-021-00485-w
347. Zhang S, Zhao BS, Zhou A, Lin K, Zheng S, Lu Z, et al. m6A demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation program. Cancer Cell. 2017;31:591-606.e6. doi: 10.1016/j.ccell.2017.02.013
348. Zhang T-T, Yi W, Dong D-Z, Ren Z-Y, Zhang Y, Du F. METTL3-mediated upregulation of FAM135B promotes EMT of esophageal squamous cell carcinoma via regulating the Wnt/β-catenin pathway. Am J Physiol Cell Physiol. 2024;327:C329-40. doi: 10.1152/ajpcell.00529.2023
349. Zhang X, Su T, Wu Y, Cai Y, Wang L, Liang C, et al. N6-Methyladenosine Reader YTHDF1 promotes stemness and therapeutic resistance in hepatocellular carcinoma by enhancing NOTCH1 expression. Cancer Res. 2024;84:827-40. doi: 10.1158/0008-5472.CAN-23-1916
350. Zhang X, Zhang X, Liu T, Zhang Z, Piao C, Ning H. METTL14 promotes migration and invasion of choroidal melanoma by targeting RUNX2 mRNA via m6A modification. J Cell Mol Med. 2022;26:5602-13. doi: 10.1111/jcmm.17577
351. Zhang Y, Liu X, Wang Y, Lai S, Wang Z, Yang Y, et al. The m6A demethylase ALKBH5-mediated upregulation of DDIT4-AS1 maintains pancreatic cancer stemness and suppresses chemosensitivity by activating the mTOR pathway. Mol Cancer. 2022;21(1):174. doi: 10.1186/s12943-022-01647-0
352. Zhang Y, Ma Z, Li C, Wang C, Jiang W, Chang J, et al. The genomic landscape of cholangiocarcinoma reveals the disruption of post-transcriptional modifiers. Nat Commun. 2022;13(1):3061. doi: 10.1038/s41467-022-30708-7
353. Zhang Z, Theler D, Kaminska KH, Hiller M, de la Grange P, Pudimat R, et al. The YTH domain is a novel RNA binding domain. J Biol Chem. 2010;285:14701-10. doi: 10.1074/jbc.M110.104711
354. Zhang Z-X, Ren P, Cao Y-Y, Wang T-T, Huang G-H, Li Y, et al. HOXD-AS2-STAT3 feedback loop attenuates sensitivity to temozolomide in glioblastoma. CNS Neurosci Ther. 2023;29:3430-45. doi: 10.1111/cns.14277
355. Zhao Y, Hu X, Yu H, Sun H, Zhang L, Shao C. The FTO mediated N6-methyladenosine modification of DDIT4 regulation with tumorigenesis and metastasis in prostate cancer. Research (Wash D C). 2024;7:0313. doi: 10.34133/research.0313
356. Zhao Y, Li Y, Zhu R, Feng R, Cui H, Yu X, et al. RPS15 interacted with IGF2BP1 to promote esophageal squamous cell carcinoma development via recognizing m6A modification. Signal Transduct Target Ther. 2023;8(1):224. doi: 10.1038/s41392-023-01428-1
357. Zhao Y, Shi Y, Shen H, Xie W. m6A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020;13(1):35. doi: 10.1186/s13045-020-00872-8
358. Zheng G, Dahl JA, Niu Y, Fedorcsak P, Huang C-M, Li CJ, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18-29. doi: 10.1016/j.molcel.2012.10.015
359. Zheng Z, Zeng X, Zhu Y, Leng M, Zhang Z, Wang Q, et al. CircPPAP2B controls metastasis of clear cell renal cell carcinoma via HNRNPC-dependent alternative splicing and targeting the miR-182-5p/CYP1B1 axis. Mol Cancer. 2024;23(1):4. doi: 10.1186/s12943-023-01912-w
360. Zhong L, Liao D, Zhang M, Zeng C, Li X, Zhang R, et al. YTHDF2 suppresses cell proliferation and growth via destabilizing the EGFR mRNA in hepatocellular carcinoma. Cancer Lett. 2019;442:252-61. doi: 10.1016/j.canlet.2018.11.006
361. Zhou G, Wang S. YTHDC2 retards cell proliferation and triggers apoptosis in papillary thyroid cancer by regulating CYLD-mediated inactivation of Akt signaling. Appl Biochem Biotechnol. 2024;196(1):588-603. doi: 10.1007/s12010-023-04540-8
362. Zhou KI, Shi H, Lyu R, Wylder AC, Matuszek Ż, Pan JN, et al. Regulation of co-transcriptional pre-mRNA splicing by m6A through the low-complexity protein hnRNPG. Mol Cell. 2019;76(1):70-81.e9. doi: 10.1016/j.molcel.2019.07.005
363. Zhou R, Ni W, Qin C, Zhou Y, Li Y, Huo J, et al. A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma. J Exp Clin Cancer Res. 2022;41(1):334. doi: 10.1186/s13046-022-02538-4
364. Zhou S, Sheng L, Zhang L, Zhang J, Wang L. METTL3/IGF2BP3-regulated m6A modification of HYOU1 confers doxorubicin resistance in breast cancer. Biochim Biophys Acta Gen Subj. 2024;1868(3):130542. doi: 10.1016/j.bbagen.2023.130542
365. Zhou X, Li C, Chen T, Li W, Wang X, Yang Q. Targeting RNA N6-methyladenosine to synergize with immune checkpoint therapy. Mol Cancer. 2023;22(1):36. doi: 10.1186/s12943-023-01746-6
366. Zhou Y, Fan K, Dou N, Li L, Wang J, Chen J, et al. YTHDF2 exerts tumor-suppressor roles in gastric cancer via up-regulating PPP2CA independently of m6A modification. Biol Proced Online. 2023;25(1):6. doi: 10.1186/s12575-023-00195-1
367. Zhou Y, Huang Q, Wu C, Xu Y, Guo Y, Yuan X, et al. m6A‑modified HOXC10 promotes HNSCC progression via co‑activation of ADAM17/EGFR and Wnt/β‑catenin signaling. Int J Oncol. 2024;64(2). doi: 10.3892/ijo.2023.5598
368. Zhou Y, Xue X, Luo J, Li P, Xiao Z, Zhang W, et al. Circular RNA circ-FIRRE interacts with HNRNPC to promote esophageal squamous cell carcinoma progression by stabilizing GLI2 mRNA. Cancer Sci. 2023;114:3608-22. doi: 10.1111/cas.15899
369. Zhou Y, Zhou X, Ben Q, Liu N, Wang J, Zhai Y, et al. GATA6-AS1 suppresses epithelial-mesenchymal transition of pancreatic cancer under hypoxia through regulating SNAI1 mRNA stability. J Transl Med. 2023;21(1):882. doi: 10.1186/s12967-023-04757-5
370. Zhou Z, Zhang B, Deng Y, Deng S, Li J, Wei W, et al. FBW7/GSK3β mediated degradation of IGF2BP2 inhibits IGF2BP2-SLC7A5 positive feedback loop and radioresistance in lung cancer. J Exp Clin Cancer Res. 2024;43(1):34. doi: 10.1186/s13046-024-02959-3
371. Zhu D, Zhou J, Zhao J, Jiang G, Zhang X, Zhang Y, et al. ZC3H13 suppresses colorectal cancer proliferation and invasion via inactivating Ras-ERK signaling. J Cell Physiol. 2019;234:8899-907. doi: 10.1002/jcp.27551
372. Zhu H, Chen K, Chen Y, Liu J, Zhang X, Zhou Y, et al. RNA-binding protein ZCCHC4 promotes human cancer chemoresistance by disrupting DNA-damage-induced apoptosis. Signal Transduct Target Ther. 2022;7(1):240. doi: 10.1038/s41392-022-01033-8
373. Zhu J, Tong H, Sun Y, Li T, Yang G, He W. YTHDF1 promotes bladder cancer cell proliferation via the METTL3/YTHDF1-RPN2-PI3K/AKT/mTOR axis. Int J Mol Sci. 2023;24(8):6905. doi: 10.3390/ijms24086905
374. Zhu T-Y, Hong L-L, Ling Z-Q. Oncofetal protein IGF2BPs in human cancer: functions, mechanisms and therapeutic potential. Biomark Res. 2023;11(1):62. doi: 10.1186/s40364-023-00499-0
375. Zhu W, Wang J-Z, Wei J-F, Lu C. Role of m6A methyltransferase component VIRMA in multiple human cancers (Review). Cancer Cell Int. 2021;21(1):172. doi: 10.1186/s12935-021-01868-1
376. Zhu Z, Zhou Y, Chen Y, Zhou Z, Liu W, Zheng L, et al. m6A Methyltransferase KIAA1429 regulates the cisplatin sensitivity of gastric cancer cells via stabilizing FOXM1 mRNA. Cancers (Basel). 2022;14(20):5025. doi: 10.3390/cancers14205025
377. Zhuang A, Gu X, Ge T, Wang S, Ge S, Chai P, et al. Targeting histone deacetylase suppresses tumor growth through eliciting METTL14-modified m6 A RNA methylation in ocular melanoma. Cancer Commun (Lond). 2023;43:1185-206. doi: 10.1002/cac2.12471
378. Zhuang C, Zhuang C, Luo X, Huang X, Yao L, Li J, et al. N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis. J Cell Mol Med. 2019;23:2163-73. doi: 10.1111/jcmm.14128
379. Zou Z, He C. The YTHDF proteins display distinct cellular functions on m6A-modified RNA. Trends Biochem Sci. 2024;49:611-21. doi: 10.1016/j.tibs.2024.04.001
 
 

Figure 1: Graphical abstract: m6A modification regulators affect biological behaviors such as cancer proliferation, metastasis, immune escape, chemoresistance and angiogenesis by regulating m6A modifications of downstream target mRNAs.

Figure 2: Signaling pathways regulated by m6A modification regulators. Red color indicates m6A regulators with oncogenic role, blue color indicates m6A regulators with anti-oncogenic role.

Figure 3: The role of m6A modification regulators in cancer. Red color indicates oncogenic regulators, blue color indicates anti-oncogenic regulators, and black color indicates regulators that have both oncogenic and anti-oncogenic effects.

 

Table 1: The function of m6A modification regulators

[*] Corresponding Author:

Liang Shang, Department of Gastrointestinal Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China, eMail: docshang@163.com